A Phase III, Open Label, Randomised, Controlled, Multi-Centre Study To Assess the Efficacy and Safety of Savolitinib Versus Sunitinib in Patients With MET-Driven, Unresectable and Locally Advanced, Or Metastatic Papillary Renal Cell Carcinoma (PRCC)
Phase: PHASE3
Conditions: Carcinoma, Carcinoma, Renal Cell, Kidney Neoplasms, Urologic Neoplasms, Kidney Diseases, Neoplasms by Site, Enzyme Inhibitors, Protein Kinase Inhibitors
Sponsor: AstraZeneca

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Clinical Study Protocol  
 
Drug Substance 
Savolitinib (AZD6094) 
 
Study Code 
D5082C00003 
 
Version 
6.0 
 
Date 
19 December 2018 
A Phase III, Open Label, Randomised, Controlled, Multi-Centre 
Study to Assess the Efficacy and Safety of Savolitinib versus 
Sunitinib in Patients with MET-Driven, Unresectable and Locally 
Advanced, or Metastatic Papillary Renal Cell Carcinoma (PRCC)
 
Sponsor:  AstraZeneca AB, 151 85 Södertälje, Sweden 

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VERSION HISTORY 
Version 6.0, 19 December 2018 
Overall changes 
A recent review of the final results of the Molecular Epidemiology Study concluded that in 
this data-set, 
 
 
It was also concluded that the 
SAVOIR study design would not benefit from a study size reassessment given the 
 
 
 
Following a review of the Molecular Epidemiology Study results, a decision, endorsed by 
the IDMC, was made to terminate recruitment into SAVOIR. 
 
Patients randomised in SAVOIR may continue to receive their assigned treatment for as 
long as they are deriving clinical benefit or until they meet a protocol-defined stopping 
criterion and must follow the study plan as outlined.  Patients already in screening (who 
have signed the ICF) will have the option to continue screening and to randomisation if 
eligible. 
 
Consequential changes for clarity have been made in multiple sections throughout the 
protocol. 
 
Changes in specific sections: 
 
Whole document: Minor formatting changes have been made throughout (eg, table 
formatting to align with AZ style guide). 
 
Section 1.4 (Study design): Rationale added as to why recruitment into SAVOIR has been 
terminated. 
Figure 1 (Study flowchart) updated to remove ‘n’ numbers from the savolitinib and 
sunitinib dosing schedule.  Abbreviations footnote also added for clarity. 
 
Section 1.5.1 (Independent Data Monitoring Committee): Rationale added as to why 
recruitment into SAVOIR has been terminated, and why an interim analysis and sample 
size-reassessment will no longer take place. 
 
Section 4.3.4 (Post study-drug follow up): Information regarding the management of 
patients’ post-final analysis has been added. 
 
Section 4.3.5 (Patient management post-final analysis): Section/information regarding the 
management of patients’ post-final analysis has been added. 

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Section 8.1 (Statistical considerations):  
Section revised to state that due to termination of recruitment into SAVOIR, all secondary 
analyses will be descriptive.  Figure 2 (Multiple testing strategy) removed, as no longer 
relevant. 
Text added regarding the updated sample size.  The sample size has been reduced from 
approximately 180 patients to approximately 50 patients. 
Rationale added as to why an interim futility analysis and sample size-reassessment will no 
longer take place. 
 
Section 8.3.1.3 (Objective Response Rate (ORR): Text revised to state that only summaries 
for ORR will be provided. 
 
Section 8.3.1.4 (Duration of Response (DoR): Text revised to state that only summaries for 
DoR will be provided. 
 
Section 8.3.1.5 (Disease control rate (DCR): Text revised to state that only summaries for 
DCR will be provided. 
 
Section 8.3.1.6 (Tumour shrinkage: Text revised to state that only summaries for tumour 
shrinkage will be provided. 
 
Section 8.3.1.9 (HRQoL and symptoms): Text revised for how the FACIT-F and FKSI-19 
questionnaire scores are calculated. 
 
Section 8.4 (Methods for statistical analyses): Table 13 (Formal statistical analyses to be 
conducted and pre-planned sensitivity analyses) removed, as no longer relevant. 
 
Section 8.4.1 (Analysis of the primary variable[s]): Section revised to clarify the analysis of 
the primary variable. 
 
Section 8.4.2 (Analysis of the secondary variable[s]): Section revised to clarify the analysis 
of ORR and DCR, DoR, OS, PFS2, and PRO analyses. 
Text revised to clarify the time period for OS and PFS2 analysis. 
 
Section 8.4.3 (Subgroup analyses): Section updated to state that no subgroup analysis will 
be performed. 
 
Section 8.4.4 (Interim analysis): Rationale added as to why an interim futility analysis will 
no longer take place.  Information regarding the original interim futility analysis has been 
removed. 

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Section 8.4.5 (Sensitivity analysis): Text regarding evaluation-time bias and attrition bias 
has been removed, as no longer relevant. 
 
Section 8.4.6.1 (Pharmacokinetics): Section revised for PK analysis. 
 
Section 9.3 (Study timetable and end of study): Information removed regarding the original 
data cut off.  Text regarding the stopping criteria for the final analysis has been added. 
 
Appendix E (Actions Required in Cases of Increases in Liver Biochemistry and Evaluation 
of Hy’s Law): Appendix revised in-line with an updated FDA requirement for reporting all 
PHL cases as SAEs. 
 
Version 5.0, 03 August 2018 
Overall changes 
Safety information and management guidelines for QTc prolongation have been updated to 
align with the Project Specific Safety Requirements, which have been updated in response 
to health authority interactions based on findings from a positive thorough QT study. 
Exclusion criteria have been updated to clarify QTcF criteria. The schedule of ECG 
assessments has been updated and additional dose modification guidance for 
savolitinib-related QTcF prolongation has been added. 
 
Changes in specific sections: 
Section 3.2 (Exclusion criterion #17): Mean resting QT interval clarified (QTcF) and 
separate QTcF criteria added for men and women. 
Section 4 (Study plan and timing of procedures), Table 1: Table text and footnotes updated 
to require triplicate ECG assessments throughout the study. 
Section 5.2.3.1 (Resting 12-lead ECG): Schedule of ECG assessments updated to require 
triplicate ECG assessments throughout the study. 
Section 6.8.1.4 (Dose modifications for savolitinib-related QTcF prolongation), Table 10: 
updated to include a consult with a cardiologist for Grade 3 and 4 toxicities and to clarify 
QTc interval (QTcF). 
 

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Version 4.0, 26 July 2018 
Overall changes 
Safety information and management guidelines for QTc prolongation have been updated to 
align with the Project Specific Safety Requirements which have been updated in response to 
findings from a positive thorough QT study. Exclusion criteria have been updated to clarify 
factors that may increase risk of QTc prolongation. Concomitant medication guidance on 
drugs known to prolong QT interval has been updated. The schedule of ECG assessments 
has been updated. 
 
Changes in specific sections: 
Whole document.  For consistency, v4.03 has been removed from CTCAE throughout the 
whole document. 
Section 1.3: Addition to benefit/risk text around QTc prolongation in response to findings 
from a thorough QT study. 
Section 3.2 (Exclusion criterion #17): Factors that may increase risk of QTc prolongation 
clarified in response to findings from a thorough QT study 
Section 3.6.2: Guidance on drugs that prolong QT interval added.  
Section 5.2.3.1: Schedule of ECG assessments updated in response to findings from a 
thorough QT study. 
Section 6.8.1: Addition of QTc prolongation to management of savolitinib-related toxicities 
in response to findings from a thorough QT study. 
Section 6.8.1.4: Addition of QTc prolongation dose modification guidance in response to 
findings from a thorough QT study. 
Section 6.8.1.5: Addition of QTc prolongation risk minimisation in response to findings 
from a thorough QT study. 
Table 1: Schedule of ECG assessments updated in response to findings from a thorough QT 
study. 
Appendix I: Addition of Appendix providing guidance on potential interactions of 
savolitinib with concomitant medications known to prolong QT interval.  
 

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Version 3.0, 09 May 2018 
Changes to the protocol are summarised below. 
Overall changes 
Inclusion and exclusion criteria have been clarified.  Text has been inserted to add clarity on 
the HBsAg, HBV DNA and HCV RNA testing.  Information on the VEGF TKIs that are 
currently most used in PRCC treatment has been updated.  Safety sections have been 
amended to align with updated product safety information and guidance.  Other minor edits 
have been made included to improve consistency. 
Changes in specific sections: 
Whole document.  For consistency, CTCAE has been updated to v4.03 throughout the 
whole document. 
Section 1.3 (Benefit/risk and ethical assessment): Addition to benefit/risk of text around 
drug-induced liver injury, hypersensitivity and pyrexia to align with updated product safety 
information and guidance. 
Sections 2.4 and 5.7.4 (exploratory endpoint): 
 
 
Section 3.1 (Inclusion criterion #3): Clarity has been added by inserting ‘Patients with 
papillary urothelial carcinoma or renal pelvis cancer of the kidney are not considered PRCC 
and are not eligible’. 
Section 3.1 (Inclusion criterion #4): Disease setting (advance setting) has been clarified. 
Section 3.2 (Exclusion criterion #3): The wording has been revised to allow 28 days 
washout period for all agents. 
Section 3.2 (Exclusion criterion #12): The type of HCV RNA test has been clarified. 
Section 3.5 (Methods for assigning treatment groups): The VEGF TKIs that are currently 
most used in PRCC treatment has been updated. 
Section 4 (Study plan and timing of procedures), Table 1: For Echocardiogram/MUGA 
procedure, an X has been added for the EOT visit as this was missing.  In addition, 
pregnancy tests have been added on Day 1 of each cycle. 

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Section 4.1 (Screening/enrolment period): Clarification that patients may be enrolled based 
on pre-existing MET-driven result if available. 
Section 5.2.1 (Laboratory safety assessments), Table 2:  Leukocyte count has been added to 
‘U-Dipstick- Leukocyte esterase’ as some sites do not perform Leukocyte esterase but 
perform a Leukocyte count instead. 
Section 5.2.1 (Laboratory safety assessments), Table 2: Footnotes have been 
inserted/revised to clarify information about the HBsAg, HBV DNA and HCV RNA tests. 
Section 5.2.5.1 (Serum or urine pregnancy test): Updated in light of a request from a Health 
Authority (Poland). 
Section 6.3.3 (Variables): CTCAE grade revised to worst 
Sections 6.8.1.1, 6.8.1.2 and 6.8.1.3: Re-ordered for clarity 
Section 6.8.1.1 (Guidance for management of non-hepatic savolitinib specific toxicities): 
Hypersensitivity and pyrexia sections updated to align with updated product safety 
information and guidance. 
Section 6.8.1.3 (Dose modifications for savolitinib-related toxicities), Table 9: Updated to 
align with updated product safety information and guidance. 
Version 2.0, 12 May 2017 
Changes to the protocol are summarised below. 
Overall changes 
Information regarding hypersensitivity and pyrexia has been added, to reflect the updated 
information in the Project Specific Safety Requirements (PSSR).  The description of PFS2 
has also been updated to clarify the intended assessments and analyses.  Other minor edits 
are included to clarify specific passages of text in the protocol. 
Changes in specific sections 
Section 3.1 (Inclusion Criteria).  Information regarding barrier contraception has been 
updated to reflect updated information in the PSSR. 
Section 4.3.3 (Follow-up for second progression on subsequent anticancer therapy after PD 
by RECIST 1.1 [PFS2]).  The description of PFS2 has been updated to clarify the intended 
assessments and analyses. 

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Section 6.8.1.3 (Guidance for management of non-hepatic savolitinib specific toxicities) has 
been created, and information regarding hypersensitivity and pyrexia has been added. 
Section 6.8.1.4 (Risk minimisation activities for identified and potential risks associated 
with savolitinib) has been updated to include pyrexia and hypersensitivity. ‘Dermatologic’ 
information has been moved to Section 6.8.1.3. 
 
Version 1.0, 20 January 2017 
Initial creation 

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This Clinical Study Protocol has been subject to a peer review according to AstraZeneca 
Standard procedures.  The Clinical Study Protocol is publicly registered and the results are 
disclosed and/or published according to the AstraZeneca Global Policy on Bioethics and in 
compliance with prevailing laws and regulations. 
 

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CLINICAL STUDY PROTOCOL SYNOPSIS 
A Phase III, Open Label, Randomised, Controlled, Multi-Centre 
Study to Assess the Efficacy and Safety of Savolitinib versus 
Sunitinib in Patients with MET-Driven, Unresectable and Locally 
Advanced, or Metastatic Papillary Renal Cell Carcinoma (PRCC) 
 
International Co-ordinating Investigator 
Toni K. Choueiri  
Dana Farber Cancer Institute  
440 Brookline Ave., Boston, MA 02215  
 
Study site(s) and number of patients planned 
Approximately 180 patients were planned to be randomised from 5 to 10 countries worldwide 
in approximately 50 to 75 sites.  Recruitment to the study was closed on 22 November 2018.  
It is now estimated that approximately 50 patients will be randomised from 7 countries. 
Study design 
This is an open label, randomised, multicentre, global Phase III study designed to evaluate the 
efficacy of savolitinib compared with sunitinib in patients with MET-driven, unresectable and 
locally advanced or metastatic papillary renal cell carcinoma (PRCC).  Patients can be 
treatment naïve or previously treated but cannot have previously received sunitinib or a MET 
inhibitor. 
Following signature of the Part 1 Informed Consent Form (ICF), the MET-driven status of the 
tumour will be determined in archival or, if necessary, fresh tumour by targeted Next 
Generation Sequencing (NGS) in the sponsor-designated central laboratory. Patients with 
confirmed MET-driven tumours, based on this testing or based on a pre-existing MET-driven 
result from the Sponsor-designated laboratory, may then sign the main study (Part 2) ICF.  
The Part 2 screening assessments must take place within 28 days of signing the ICF for Part 2.  
Randomisation must take place within 28 days of signing the ICF for Part 2.  Patients who 
fulfil all the eligibility criteria will be randomised in a ratio of 1:1 to receive savolitinib 

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(600 mg for patients ≥50 kg and 400 mg for patients <50 kg PO QD) or sunitinib (50 mg PO 
QD).  Patients will be stratified based on International Metastatic RCC Database Consortium 
(IMDC) risk category as well as whether they are treatment naive vs. previously treated with 
or without a VEGF-TKI. For the purposes of planning, a 6-week period will be called a 
“cycle”.  Treatment with sunitinib will be given daily for 4 weeks on/2 weeks off. Treatment 
with savolitinib will be given continuously.  There is no maximum duration of treatment and 
patients will continue to receive study medication until one of the discontinuation criteria are 
met. 
Following randomisation, patients will attend scheduled study visits as outlined in the study 
plan. Efficacy will be assessed by objective tumour assessments at baseline and every 6 weeks 
(±7 days) during the first year (at the start of each cycle) and then every 12 weeks thereafter 
until disease progression as defined by Response Evaluation Criteria in Solid Tumours 
(RECIST) 1.1 and confirmed by Blinded Independent Central Review (BICR).  Patients will 
receive study treatment until one of the treatment discontinuation criteria is met; there is no 
maximum duration of treatment. 
Regardless of initial treatment, patients will have two options for post-progression therapy 
following BICR-confirmation of progressive disease (PD): 
1 
Receive subsequent non-study anti-cancer therapy that does not contravene local practice. 
2 
Continue to receive the assigned treatment as long as in the opinion of the investigator, 
the patient is deriving benefit and the patient meets the original eligibility criteria in terms 
of Performance Status and laboratory values.  This decision must be discussed with and 
approved by the AstraZeneca study physician.  Such patients will continue to undergo 
monitoring as per the Study Plan (Table 1). 
 
There will be no cross-over.  
Following discontinuation of study medication for PD by RECIST 1.1 as determined by 
Investigator assessment, patients that started on subsequent cancer therapy post-progression 
will continue to be followed at least every 12 weeks by investigator assessment for 
documentation of second progression.  Determination of PD for second progression-free 
survival (PFS2) will be by institutional call.  Patients who choose to continue on study therapy 
after PD as determined by investigator assessment will not be considered to have a second 
progression-free survival (PFS) event until they discontinue study medication and progress on 
subsequent anti-cancer treatment. 
In the Overall Survival (OS) follow-up period following PFS2, all subsequent therapies and 
vital status will be documented at least every 12 weeks until death, lost to follow-up, 
withdrawal of consent, or end of study, whichever comes first. 

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A recent review of the final results of the Molecular Epidemiology Study (MES) concluded 
that in this data-set, 
 
 
  It was also concluded that the 
SAVOIR study design would not benefit from a study size reassessment 
 
 
 
Following a review of the MES results, a decision, endorsed by the Independent Data 
Monitoring Committee (IDMC), was made to terminate recruitment into SAVOIR. 
Patients randomised in SAVOIR may continue to receive their assigned treatment for as long 
as they are deriving clinical benefit or until they meet a protocol-defined stopping criterion 
and must follow the study plan as outlined.  Patients already in screening (who have signed 
the ICF) will have the option to continue screening and to be randomised if eligible. 
Further information can be found in the statistical methods section below. 
Objectives 
Primary Objective: 
Outcome Measure: 
To determine the efficacy of savolitinib when 
compared to sunitinib in patients with 
MET-driven, unresectable and locally advanced, 
or metastatic PRCC  
• 
PFS (time to earliest progression as defined by 
RECIST 1.1 and confirmed by BICR, or death) 
 
Secondary Objective: 
Outcome Measure: 
To compare the efficacy of savolitinib versus 
sunitinib in patients with MET-driven, 
unresectable and locally advanced, or metastatic 
PRCC  
• 
Overall Survival (OS) 
• 
Objective Response Rate (ORR), duration of 
response (DoR) and best percentage change in 
tumour size by BICR using RECIST 1.1 criteria   
• 
Disease Control Rate (DCR) at 6 and 12 months 
To assess the impact of savolitinib and sunitinib 
on disease related symptoms and health-related 
QOL in this patient population  
• 
Mean change from baseline in FKSI-19 and 
FACIT-F scores 
To evaluate the pharmacokinetics of savolitinib 
in this patient population 
• 
PK concentration data 
Safety Objective: 
Outcome Measure: 
To evaluate the safety and tolerability of 
savolitinib in relation to sunitinib 
• 
Adverse events [AEs] and serious adverse events 
[SAE] as characterised and graded by National 
Cancer Institute [NCI] Common Terminology 
Criteria for Adverse Event [CTCAE], collection of 
clinical chemistry/haematology parameters, liver 
function tests, echocardiograms and 
electrocardiograms (ECGs), vital signs including 
blood pressure (BP) and heart rate 

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Exploratory Objective: 
Outcome Measure: 
To compare the efficacy of savolitinib versus 
sunitinib in patients with MET-driven, 
unresectable and locally advanced, or metastatic 
papillary renal cell carcinoma PRCC 
• 
Time from randomisation to objective disease 
progression on subsequent anti-cancer therapy 
following PD by RECIST 1.1 on study medication, 
or death (PFS2) 
To assess the impact of savolitinib vs. sunitinib 
on patient reported AEs 
• 
Collection of PRO CTCAE symptoms  
To investigate the health economic impact of 
treatment and the disease on hospital related 
resource use and health state utility 
• 
Number, type and reason for hospitalisations and 
unscheduled clinic visits, procedures undertaken and 
length of hospital inpatient stays  
• 
Health state response and utility index derived from 
the EQ-5D-5L 
 
 
  
 
 
 
 
To collect and store DNA (according to each 
country’s local and ethical procedures) for future 
exploratory research into genes/genetic variation 
that may influence response (ie, distribution, 
safety, tolerability and efficacy) to study 
treatments and or susceptibility to disease 
(optional) 
• 
Pharmacogenetic analyses on blood samples  
 
 
 
  
 
The exploratory analyses may not be reported in the clinical study report (CSR).  They may be 
reported separately and may also form part of a pooled analysis with other studies.  
Target patient population 
The target population for this study includes previously treated or untreated patients with 
MET-driven, unresectable and locally advanced, or metastatic PRCC without co-occurring FH 
or VHL mutations.  Patients cannot have previously received sunitinib or a MET-inhibitor. 
Confirmation of MET-driven PRCC without co-occurring FH or VHL mutations by a 
validated NGS assay in the sponsor-designated central laboratory is required prior to study 
entry.  
Duration of treatment 
Patients will receive either savolitinib or sunitinib until one of the treatment discontinuation 
criteria is met.  There is no maximum duration of treatment.   

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Investigational product, dosage and mode of administration 
Savolitinib will be administered continuously as three 200 mg tablets by mouth (PO) with a 
meal once daily (QD) (for patients ≥50 kg) or two 200 mg tablets PO with a meal QD (for 
patients <50 kg).  The comparator will be sunitinib, given as two 25 mg capsules PO daily, 
with or without food for 4 weeks on/ 2 weeks off.  
Statistical methods 
The initial assumption was that the true treatment effect had a hazard ratio (HR) of 0.6 (which 
would have translated to an approximate 3-month improvement in median PFS over an 
assumed 4-month median PFS for MET-driven patients on sunitinib, assuming PFS was 
exponentially distributed), 121 PFS events confirmed by BICR would have had to have been 
observed for the study to have 80% power to show a statistically significant difference in PFS 
at the two-sided 5% level.  The smallest treatment difference that would have been statistically 
significant at the final analysis was a PFS HR of 0.69. Assuming 67% maturity, 180 patients 
would have been needed to be randomised.  An interim futility analysis of PFS was planned to 
be conducted when a total of approximately 36 BICR-confirmed PFS events had been 
observed (30% of 121 PFS events, which was estimated to occur 17 months after the first 
patient had been randomised).  Following IDMC endorsement to terminate recruitment into 
SAVOIR, the interim analysis will not occur.  However, interim reviews of safety data by the 
IDMC will continue until end of study. 
The final analysis of all endpoints will be conducted at the earliest time when the following 
2 criteria are met: 
1 
36 PFS events by investigator assessment 
2 
The opportunity to have at least 7.5 months follow-up from randomisation 
 
If criterion #1 has not been met 12 months after last subject in, the final analysis will be 
performed. 
The primary statistical analysis for efficacy will be carried out in the intent-to-treat 
population.  Treatment effect will be compared between treatment groups on the basis of 
randomised treatment, regardless of the treatment actually received.  When assessing safety 
and tolerability, summaries will be produced based on the Safety Analysis Set.  This will 
include all patients who receive at least one dose of randomised treatment (savolitinib or 
sunitinib).  The safety data will be summarised descriptively and difference between treatment 
arms will not be tested for statistical significance. 
Primary endpoint (PFS) analysis will be conducted using a log rank test stratified by baseline 
stratification factors, providing that there are enough events in each stratum.  The stratified 
HR together with its 95% confidence interval (CI) and p-value will be presented (an HR <1 

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will favour savolitinib).  The primary endpoint PFS data will be based on tumour assessments 
by a blinded independent central review (BICR) of disease progression by RECIST 1.1.  In 
addition, a sensitivity analysis will be performed using the investigator-recorded assessments. 
Due to termination of recruitment into SAVOIR, all secondary endpoints will be descriptive.  
No subgroup analysis will be performed. 
Objective tumour response rates and duration of response based on BICR using RECIST 1.1 
will be presented for the two treatment arms. 
Time from randomisation to investigator-assessed second progression on subsequent 
non-study anti-cancer therapy following PD using RECIST 1.1 while on study medication, or 
death (PFS2) will be summarised, and Kaplan Meier plots will be provided. 
Appropriate summaries of exploratory outcome variables will be produced and compared 
across the two treatment arms. 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
Following IDMC endorsement to terminate recruitment into SAVOIR, a sample 
size-reassessment will no longer be performed. 

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TABLE OF CONTENTS 
PAGE 
TITLE PAGE ............................................................................................................................. 1 
VERSION HISTORY ............................................................................................................... 2 
CLINICAL STUDY PROTOCOL SYNOPSIS ...................................................................... 10 
TABLE OF CONTENTS ........................................................................................................ 16 
LIST OF TABLES .................................................................................................................. 20 
LIST OF FIGURES ................................................................................................................. 21 
LIST OF APPENDICES ......................................................................................................... 21 
1. 
INTRODUCTION ................................................................................................ 27 
1.1 
Background and rationale for conducting this study ............................................ 27 
1.1.1 
Renal cell carcinoma............................................................................................. 27 
1.1.2 
PRCC and MET pathway ..................................................................................... 28 
1.1.3 
Savolitinib/AZD6094 (HMPL-504) ..................................................................... 29 
1.1.3.1 
Pharmacokinetics .................................................................................................. 29 
1.1.3.2 
Pharmacology and safety ...................................................................................... 29 
1.1.3.3 
Clinical antitumour activity data in patients with PRCC...................................... 29 
1.1.3.4 
Clinical monotherapy safety data ......................................................................... 30 
1.2 
Rationale for study design, doses and control groups .......................................... 31 
1.2.1 
Research hypothesis.............................................................................................. 31 
1.2.2 
Rationale for Savolitinib in PRCC ....................................................................... 31 
1.2.3 
Rationale for sunitinib as comparator ................................................................... 31 
1.2.4 
Rationale for line-agnostic study .......................................................................... 32 
1.2.5 
Rationale for exclusion of patients with co-occurring FH/VHL mutations .......... 32 
1.3 
Benefit/risk and ethical assessment ...................................................................... 33 
1.4 
Study design ......................................................................................................... 34 
1.5 
Study governance and oversight ........................................................................... 39 
1.5.1 
Independent Data Monitoring Committee ............................................................ 39 
2. 
STUDY OBJECTIVES ........................................................................................ 40 
2.1 
Primary objective .................................................................................................. 40 
2.2 
Secondary objectives ............................................................................................ 40 
2.3 
Safety objectives ................................................................................................... 40 
2.4 
Exploratory objectives .......................................................................................... 40 
3. 
PATIENT SELECTION, ENROLMENT, RANDOMISATION, 
RESTRICTIONS, DISCONTINUATION AND WITHDRAWAL .................... 41 
3.1 
Inclusion criteria ................................................................................................... 41 
3.2 
Exclusion criteria .................................................................................................. 43 
3.3 
Patient enrolment and randomisation ................................................................... 45 

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3.4 
Procedures for handling incorrectly enrolled or randomised patients .................. 46 
3.5 
Methods for assigning treatment groups .............................................................. 46 
3.6 
Restrictions ........................................................................................................... 47 
3.6.1 
Need for contraception ......................................................................................... 47 
3.6.2 
Prohibited concomitant medications and treatments ............................................ 48 
3.7 
Post-progression therapy ...................................................................................... 49 
3.8 
Discontinuation of investigational product ........................................................... 49 
3.8.1 
Procedures for discontinuation of a patient from study treatment prior to 
BICR-confirmed PD ............................................................................................. 50 
3.9 
Criteria for withdrawal from the study ................................................................. 51 
3.9.1 
Screen failures ...................................................................................................... 51 
3.9.2 
Withdrawal of the informed consent .................................................................... 51 
3.10 
Discontinuation of the study ................................................................................. 52 
4. 
STUDY PLAN AND TIMING OF PROCEDURES ........................................... 52 
4.1 
Screening/enrolment period .................................................................................. 60 
4.2 
Treatment period ................................................................................................... 60 
4.3 
Post study-drug follow up ..................................................................................... 60 
4.3.1 
End of Treatment (EOT) ....................................................................................... 60 
4.3.2 
Safety follow-up ................................................................................................... 61 
4.3.3 
Follow-up for second progression on subsequent anti-cancer therapy after PD 
by RECIST 1.1 (PFS2) ......................................................................................... 61 
4.3.4 
Overall survival follow-up .................................................................................... 62 
4.3.5 
Patient management post-final analysis................................................................ 62 
5. 
STUDY ASSESSMENTS .................................................................................... 63 
5.1 
Efficacy assessments ............................................................................................ 63 
5.1.1 
Tumour assessments by CT or MRI scans (RECIST 1.1) .................................... 63 
5.1.2 
Tumour evaluation ................................................................................................ 64 
5.1.3 
Central reading of scans/BICR ............................................................................. 64 
5.2 
Safety assessments ................................................................................................ 65 
5.2.1 
Laboratory safety assessments .............................................................................. 65 
5.2.2 
Physical examination ............................................................................................ 67 
5.2.3 
ECG, ECHO/MUGA ............................................................................................ 67 
5.2.3.1 
Resting 12-lead ECG ............................................................................................ 67 
5.2.3.2 
ECHO or MUGA .................................................................................................. 67 
5.2.4 
Vital signs ............................................................................................................. 68 
5.2.4.1 
Pulse and blood pressure ...................................................................................... 68 
5.2.4.2 
Body temperature.................................................................................................. 68 
5.2.5 
Other safety assessments ...................................................................................... 68 
5.2.5.1 
Serum or urine pregnancy test .............................................................................. 68 
5.3 
Other assessments ................................................................................................. 68 
5.3.1 
Patient Reported Outcomes .................................................................................. 68 
5.3.1.1 
Functional Assessment of Chronic Illness Therapy – Fatigue ............................. 70 
5.3.1.2 
Functional Assessment of Cancer Therapy Kidney Symptom Index-19.............. 70 

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5.3.1.3 
European Quality of Life-5 Dimensions-5 Levels................................................ 70 
5.3.1.4 
PRO CTCAE ........................................................................................................ 70 
5.3.2 
Hospital resource use ............................................................................................ 71 
5.4 
Pharmacokinetics .................................................................................................. 71 
5.4.1 
Collection of samples ........................................................................................... 71 
5.4.2 
Determination of drug concentration .................................................................... 72 
5.4.3 
Storage and destruction of pharmacokinetic samples ........................................... 72 
5.5 
Pharmacodynamics ............................................................................................... 73 
5.5.1 
Collection of samples ........................................................................................... 73 
5.6 
Pharmacogenetics (Appendix C) .......................................................................... 73 
5.7 
Biomarker analysis ............................................................................................... 73 
5.7.1 
NGS analysis to determine MET-driven status of tumour biopsy sample ........... 73 
5.7.2 
Collection, analysis and reporting of tumour samples.......................................... 74 
5.7.3 
Exploratory use of data generated from the sponsor-designated central 
laboratory testing of tumour samples ................................................................... 74 
 
 
 
 
 
 
 
5.7.7 
Collection of tumour samples for exploratory analysis at disease progression 
(optional)............................................................................................................... 77 
5.7.8 
Storage, re-use and destruction of biological samples.......................................... 77 
5.7.9 
Labelling and shipment of biological samples (Appendix B) .............................. 77 
5.7.10 
Chain of custody of biological samples ................................................................ 77 
5.7.11 
Withdrawal of Informed Consent for donated biological samples ....................... 78 
5.7.12 
Volume of blood ................................................................................................... 78 
6. 
SAFETY REPORTING AND MEDICAL MANAGEMENT ............................. 79 
6.1 
Definition of adverse events ................................................................................. 79 
6.1.1 
AEs of special interest – hepatic disorders ........................................................... 80 
6.2 
Definitions of serious adverse event ..................................................................... 81 
6.3 
Recording of adverse events ................................................................................. 81 
6.3.1 
Time period for collection of adverse events ....................................................... 81 
6.3.2 
Follow-up of unresolved adverse events .............................................................. 81 
6.3.3 
Variables ............................................................................................................... 82 
6.3.4 
Causality collection .............................................................................................. 83 
6.3.5 
Adverse events based on signs and symptoms ..................................................... 83 
6.3.6 
Adverse events based on examinations and tests ................................................. 83 
6.3.7 
Hy’s Law .............................................................................................................. 84 
6.3.8 
Disease progression .............................................................................................. 84 
6.4 
Reporting of serious adverse events ..................................................................... 84 
6.5 
Overdose ............................................................................................................... 85 
6.6 
Pregnancy ............................................................................................................. 85 
6.6.1 
Maternal exposure ................................................................................................ 86 
6.6.2 
Paternal exposure .................................................................................................. 86 

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6.7 
Medication error ................................................................................................... 86 
6.8 
Management of study medication-related toxicities - dose reductions and 
modifications ........................................................................................................ 88 
6.8.1 
Management of savolitinib-related toxicities ....................................................... 88 
6.8.1.1 
Guidance for management of savolitinib specific toxicities................................. 89 
6.8.1.2 
Dose modification due to savolitinib-related hepatotoxicity ................................ 89 
6.8.1.3 
Dose modifications due to other savolitinib-related toxicity ................................ 91 
6.8.1.4 
Dose modifications for savolitinib-related QTcF prolongation............................ 92 
6.8.1.5 
Risk minimisation activities for identified and potential risks associated with 
savolitinib ............................................................................................................. 92 
6.8.2 
Management of sunitinib-related toxicities .......................................................... 95 
6.8.2.1 
Risk minimisation activities for risks associated with sunitinib ........................... 95 
7. 
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS ................... 97 
7.1 
Identity of study medications ............................................................................... 97 
7.2 
Dose and treatment regimens................................................................................ 97 
7.2.1 
Savolitinib ............................................................................................................. 97 
7.2.2 
Sunitinib ................................................................................................................ 98 
7.3 
Labelling ............................................................................................................... 99 
7.4 
Storage .................................................................................................................. 99 
7.5 
Compliance ........................................................................................................... 99 
7.6 
Accountability....................................................................................................... 99 
7.7 
Concomitant and other treatments ........................................................................ 99 
7.7.1 
Permitted concomitant medications and treatments ............................................. 99 
7.7.2 
Restrictions based on clinical pharmacology for both study medications .......... 100 
7.7.3 
Other concomitant treatment .............................................................................. 101 
8. 
STATISTICAL ANALYSES BY ASTRAZENECA ......................................... 101 
8.1 
Statistical considerations .................................................................................... 101 
8.2 
Definitions of analysis sets ................................................................................. 102 
8.2.1 
Full analysis set................................................................................................... 102 
8.2.2 
Safety analysis set ............................................................................................... 102 
8.2.3 
PK analysis set .................................................................................................... 102 
8.3 
Outcome measures for analyses.......................................................................... 103 
8.3.1 
Calculation or derivation of efficacy variables ................................................... 103 
8.3.1.1 
Blinded Independent Central Review (BICR) of RECIST-based assessments .. 103 
8.3.1.2 
Progression-Free Survival (PFS) ........................................................................ 103 
8.3.1.3 
Objective Response Rate (ORR) ........................................................................ 104 
8.3.1.4 
Duration of Response (DoR) .............................................................................. 104 
8.3.1.5 
Disease control rate (DCR) ................................................................................. 104 
8.3.1.6 
Tumour shrinkage ............................................................................................... 104 
8.3.1.7 
Overall Survival (OS) ......................................................................................... 105 
8.3.1.8 
Time to second progression or death (PFS2) ...................................................... 105 
8.3.1.9 
HRQoL and symptoms ....................................................................................... 105 
8.4 
Methods for statistical analyses .......................................................................... 106 

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8.4.1 
Analysis of the primary variable (s) ................................................................... 106 
8.4.2 
Analysis of the secondary variable(s) ................................................................. 106 
8.4.3 
Subgroup analysis ............................................................................................... 108 
8.4.4 
Interim analysis ................................................................................................... 108 
8.4.5 
Sensitivity analysis ............................................................................................. 108 
8.4.6 
Exploratory analyses ........................................................................................... 108 
8.4.6.1 
Pharmacokinetics ................................................................................................ 108 
8.4.6.2 
Pharmacogenetic research and statistical methods, and determination of 
sample size .......................................................................................................... 108 
9. 
STUDY AND DATA MANAGEMENT BY ASTRAZENECA ....................... 109 
9.1 
Training of study site staff .................................................................................. 109 
9.2 
Monitoring of the study ...................................................................................... 109 
9.2.1 
Source data.......................................................................................................... 109 
9.2.2 
Study agreements ................................................................................................ 110 
9.2.3 
Archiving of study documents ............................................................................ 110 
9.3 
Study timetable and end of study........................................................................ 110 
9.4 
Data management by AstraZeneca ..................................................................... 110 
9.4.1 
Serious Adverse Event (SAE) reconciliation ..................................................... 111 
9.4.2 
Data management of genotype data .................................................................... 111 
9.4.3 
Data associated with human biological samples ................................................ 111 
9.4.4 
Management of external data.............................................................................. 111 
10. 
ETHICAL AND REGULATORY REQUIREMENTS ..................................... 112 
10.1 
Ethical conduct of the study ............................................................................... 112 
10.2 
Patient data protection ........................................................................................ 112 
10.3 
Ethics and regulatory review .............................................................................. 112 
10.4 
Informed consent ................................................................................................ 113 
10.5 
Changes to the Clinical Study Protocol and Informed Consent Form ............... 114 
10.6 
Audits and inspections ........................................................................................ 114 
11. 
LIST OF REFERENCES .................................................................................... 115 
 
LIST OF TABLES 
Table 1 
Study schedule: Screening, On Study Treatment, Discontinuation and 
Follow-up .................................................................................................... 53 
Table 2 
Standard Laboratory Safety Assessment Panel ........................................... 66 
Table 3 
Pharmacokinetic savolitinib blood sampling schedule ............................... 72 
 
 
 
 
 
 
 
 

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Table 7 
Volume of blood to be drawn from each patient in the first 24 weeks ....... 79 
Table 8 
Dose level reductions of study medications ................................................ 88 
Table 9 
Dose modifications for savolitinib-related toxicities .................................. 91 
Table 10 
Dose modifications for savolitinib-related QTcF prolongation .................. 92 
Table 11 
Dose modifications for sunitinib-related toxicities (including hepatic) ...... 95 
Table 12  
IP strength and manufacturer ...................................................................... 97 
 
LIST OF FIGURES 
Figure 1 
Study flowchart ........................................................................................... 38 
 
LIST OF APPENDICES 
Appendix A 
Additional Safety Information .................................................................. 119 
Appendix B 
International Airline Transportation Association (IATA) 6.2 Guidance 
Document .................................................................................................. 121 
Appendix C 
Genetic Research ....................................................................................... 122 
Appendix D 
Acceptable Birth Control Methods ........................................................... 125 
Appendix E 
Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law ............................................................................ 126 
Appendix F 
Guidance for Evaluation of Objective Tumour Response Using RECIST 
1.1 Criteria (Response Evaluation Criteria in Solid Tumours) ................. 131 
Appendix G 
Performance Status (Karnofsky Scale) ..................................................... 139 
Appendix H 
Guidance Regarding Potential Interactions of Savolitinib with 
Concomitant Medications ......................................................................... 140 
Appendix I 
Guidance Regarding Potential Interactions of Savolitinib with 
Concomitant Medications Known to Prolong QT Interval ....................... 145 
Appendix J 
Patient Reported Outcomes ....................................................................... 146 
Appendix K 
Stages of Heart Failure – New York Heart Association Classification .... 157 

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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
The following abbreviations and special terms are used in this study Clinical Study Protocol. 
Abbreviation or special 
term 
Explanation 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
Anti-HBc 
Anti-hepatitis B core antigen 
aPTT 
Activated partial thromboplastin time 
ASCO 
American Society of Clinical Oncology 
AST 
Aspartate aminotransferase 
ATP 
Adenosine triphosphate 
AZRand 
AstraZeneca Randomisation system 
BCRP 
Breast Cancer Resistance Protein 
BICR 
Blinded Independent Central Review 
BID 
Twice a day 
BP 
Blood pressure 
eCRF 
Electronic Case Report Form  
CA-125 
cancer antigen 125 
ccRCC 
Clear cell Renal Cell Carcinoma 
CHF 
Congestive Heart Failure 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration 
Cmax 
Maximum serum concentration 
CR 
Complete Response  
CRO 
Contract Research Organisation 
CSA 
Clinical Study Agreement 
CSP 
Clinical Study Protocol 
CSR 
Clinical Study Report 
CT 
Computed Tomography 
CTA 
Clinical Trial Assay 
CTCAE 
Common Terminology Criteria for Adverse Event 
 
 
DCR 
Disease Control Rate 
DES 
Data Entry Site 

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Abbreviation or special 
term 
Explanation 
DGR 
Dangerous Goods Regulations 
DHEA 
Dehydroepiandrosterone 
DILI 
Drug-induced liver injury  
dL 
Decilitre 
DNA 
Deoxyribonucleic acid  
DoR 
Duration of response 
DUS 
Disease under study 
DVT 
Deep vein thrombosis 
EC 
Ethics Committee, synonymous to Institutional Review Board (IRB) and 
Independent Ethics Committee (IEC) 
ECG 
Electrocardiogram   
ECHO 
Echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EDTA 
Ethylenediaminetetraacetic acid 
EE 
Ethinyl Estradiol 
EM 
Erythema multiforme 
ePRO 
Electronic Patient Reported Outcomes 
EOT 
End of Treatment  
EQ-5D-5L 
European Quality of Life-5 Dimensions-5 Levels 
EQ-VAS 
EuroQoL-Visual Analogue Scale 
EuroQoL 
European Quality of Life 
FACIT-F 
Functional Assessment of Chronic Illness Therapy – Fatigue 
FACT-G 
Functional Assessment of Cancer Therapy-General 
FAS 
Full analysis set 
FDG-PET 
Fluorodeoxyglucose- Positron Emission Tomography 
FFPE 
Formalin Fixed and Paraffin Embedded 
FH 
Fumarate Hydratase 
FKSI-19 
Cancer Therapy Kidney Symptom Index-19 
FSH 
Follicle stimulating hormone 
FTIH 
First Time in Human 
FU 
Follow up 
GCP 
Good Clinical Practice 
GFR 
Glomerular filtration rate 
GLP 
Good Laboratory Practice 
GM-CSF 
Granulocyte-macrophage colony stimulating factor 

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Abbreviation or special 
term 
Explanation 
GMP 
Good Manufacturing Practice 
HBsAg 
Surface antigen of the hepatitis B virus (HBV) 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 
HDPE 
High-density polyethylene 
Hgb 
Haemoglobin 
HGF 
Hepatocyte growth factor 
HIV 
Human immunodeficiency virus 
HL 
Hy’s Law 
HOSPAD 
Hospital Admissions module 
HR 
Hazard ratio 
HRQoL 
Health Related Quality of Life 
i.v. 
Intravenous 
IATA 
International Airline Transportation Association 
IB 
Investigator Brochure 
ICH 
International Conference on Harmonisation 
IC50 
Fifty percent of the maximal inhibitory concentration 
ICF 
Informed Consent Form 
IDMC 
Independent Data Monitoring Committee 
IMDC 
International Metastatic RCC Database Consortium 
IMP 
Investigational Medicinal Product 
INR 
International Normalisation Ratio 
IP 
Investigational Product  
IRB 
Institutional Review Board 
ITT 
Intention-to-treat  
IUD 
Intra-uterine device 
IVRS 
Interactive Voice Response System 
IWRS 
Interactive Web Response System 
LDH 
Lactate Dehydrogenase 
LIMS 
Laboratory Information Management System 
LOEL 
Lowest observed effect level 
LSLV 
Last Subject Last Visit 
LVEF 
Left Ventricular Ejection Fraction 
MDRD 
Modification of Diet in Renal Disease 
MedDRA 
Medical Dictionary for Regulatory Activities 

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Abbreviation or special 
term 
Explanation 
MES 
Molecular Epidemiology Study 
mL 
Millilitre 
Mm 
Millimetre 
mmHg  
Millimetre of mercury  
MRI 
Magnetic Resonance Imaging 
mTOR 
Mammalian target of rapamycin 
MUGA 
Multigated acquisition scan 
NA 
Not applicable 
NADPH 
Nicotinamide adenine dinucleotide phosphate-oxidase 
NCI 
National Cancer Institute 
NE 
Not Evaluable  
NGS 
Next Generation Sequencing 
nM 
Nanomolar 
NOEL 
No observed effect level 
NTL 
Non-target Lesion 
NYHA 
New York Heart Association 
ORR 
Objective Response Rate 
OS 
Overall survival 
PAS 
Primary Analysis Set 
PD 
Progression of Disease  
PDA 
Personal Data Assistant 
PDL-1 
Programmed cell Death Ligand-1 
PFS 
Progression-free survival 
PFS2 
Second progression-free survival 
Pgp 
P-glycoprotein 
PGx 
Pharmacogenetic  
PHL 
Potential Hy’s Law 
PI 
Principal Investigator  
PK 
Pharmacokinetic 
PO 
Orally 
PR 
Partial Response 
PRCC 
Papillary renal cell carcinoma 
PRO 
Patient Reported Outcomes 
PRO-CTCAE 
The Patient-Reported Outcomes version of the Common Terminology Criteria for 
Adverse Events 

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Abbreviation or special 
term 
Explanation 
PTT 
Partial thromboplastin time 
QD 
Once a day 
QT 
ECG interval measured from the onset of the QRS complex to the end of the T 
wave 
QTc 
QT interval corrected for heart rate 
QTcF 
QT interval corrected for heart rate using Fridericia’s Correction Formula 
RANK 
Receptor activator of nuclear factor kappa 
RCC 
Renal cell carcinoma 
RECIST 
Response Evaluation Criteria in Solid Tumours 
RNA 
Ribonucleic acid 
RR 
Response rate 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SBP 
Systolic blood pressure 
SD 
Stable Disease 
SJS 
Stevens-Johnson syndrome 
SMQ 
Standard MedDRA Query 
SPC 
Summary of Product Characteristics 
SPF 
Sun Protection Factor 
T1/2 
Half-life  
TBL 
Total Bilirubin 
TCGA 
The Cancer Genome Atlas Research Network 
TEN 
Toxic epidermal necrolysis 
TKIs 
Tyrosine kinase inhibitors 
TL 
Target Lesion 
tmax 
Time to reach maximum concentration 
ULN 
Upper limit of normal 
UV 
Ultraviolet 
VAS 
Visual analogue scale 
VEGF 
Vascular endothelial growth factor 
VEGF-TKI 
Vascular endothelial growth factor receptor tyrosine kinase inhibitor 
VHL  
Von Hippel–Lindau  
w/o 
Without 
WBDC 
Web-based data capture 
WHO 
World Health Organization 

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Abbreviation or special 
term 
Explanation 
WoCBP 
Women of Child Bearing Potential 
1. 
INTRODUCTION 
1.1 
Background and rationale for conducting this study 
1.1.1 
Renal cell carcinoma 
Renal cell carcinoma (RCC) accounts for approximately 3% of all malignancies in adults 
(Bellmunt and Dutcher 2013).  An estimated 62,700 Americans will be newly diagnosed with 
cancer of the kidney and renal pelvis and 14,240 Americans will die of this disease in the 
United States in 2016 (Siegel RL, Miller KD, Jemal A. 2016). Worldwide, 270,000 new 
patients are diagnosed each year and up to 116,000 deaths occur due to RCC (Ljungberg et al 
2011). RCC is more common in men than in women and usually occurs between 50 to 
70 years of age. Renal cell carcinoma is a heterogeneous disease made up of several 
histological subtypes with different genetic and biochemical characteristics.  Among the 
histologic variants of RCC, clear cell RCC (ccRCC) is the most common, accounting for 75% 
to 90% of all renal malignancies.  Papillary RCC (PRCC) is the most common of the 
non-clear cell renal carcinomas, accounting for 10% to 15% (Bellmunt and Dutcher 2013). 
At present, there is no approved therapy indicated specifically for the treatment of PRCC, and 
therefore patients with PRCC are treated in a similar manner as clear-cell RCC patients.  In 
addition, there has never been a rigorously controlled biomarker-based clinical trial to help 
inform the selection of treatment for patients with either ccRCC or PRCC (Bellmunt and 
Dutcher 2013). Chemotherapy trials have shown RCC to be resistant to cytotoxic treatments 
(Motzer et al 2002).  Advances in ccRCC treatment have included anti-tumour agents that 
function as inhibitors of vascular endothelial growth factor (VEGF) angiogenesis and the 
mammalian target of rapamycin (mTOR).  Approved agents targeting the VEGF pathway 
include, sunitinib, sorafenib, bevacizumab (in combination with IFN-α), pazopanib, and 
axitinib, and for targeting the mTOR pathway, temsirolimus, and everolimus.  The 
combination of a VEGF-inhibitor and an mTOR inhibitor, lenvantinib and everolimus, was 
approved in 2016, as was cabozantinib, a small molecule with both VEGF- and MET- 
inhibitory properties.  In 2015 nivolumab, an agent targeting the PD 1/programmed cell death 
ligand-1 (PDL-1) pathway, was approved.  The trials that led to the approval of these agents 
almost exclusively included patients with ccRCC.   
Studies exploring treatment efficacy in patients with both ccRCC and non-ccRCC, including 
PRCC suggest that current therapies allow patients with ccRCC to live longer than those with 
non-ccRCC (Kroeger et al 2013, Vera-Badillo et al 2015).  A large retrospective analysis 
conducted in the International Metastatic RCC Database Consortium (IMDC) (Kroeger et al 
2013) analysed 2370 patients who received first line targeted therapy between 2003 and 2012.  

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The prognosis for non-ccRCC was found to be worse than that of ccRCC.  The median OS for 
PRCC patients was 14.0 months (95% CI 10.9, 17.1) and for ccRCC patients was 22.3 months 
(95% CI 20.7, 23.5).  After adjustment for IMDC risk group, the HR for death was 1.57 (95% 
CI: 1.27 – 1.94; p<0.0001). 
Taking into consideration the totality of the published evidence, the clinical practice 
guidelines of the European Society of Medical Oncology (Escudier et al 2014) and the 
National Comprehensive Cancer Network (NCCN; v. 2.2017, dated October 31, 2016) both 
recommend a clinical trial as the preferred option for treatment of advanced or metastatic 
PRCC patients.  The 2014 guidelines for the European Association of Urology indicate that 
everolimus and sunitinib “remain options in this population, with a preference for sunitinib”, 
but also indicate that patients should be referred for clinical trials where appropriate 
(Ljungberg et al 2015). 
1.1.2 
PRCC and MET pathway 
With better understanding of tumour biology, there is now evidence that the MET pathway in 
patients with PRCC is often activated, which is thought to drive disease progression.  There is 
a growing body of evidence suggesting that MET abnormalities are not only a differentiating 
characteristic of PRCC, but may be, in at least a subset of PRCC, a therapeutic target (The 
Cancer Genome Atlas Research Network 2016).  Specifically, one of the underlying 
pathogenic features of PRCC is dysregulation of the MET signalling pathway, which is 
involved in cell motility, proliferation, angiogenesis, and cell survival.  Overexpression of 
cytoplasmic MET has been reported in approximately 80% of papillary tumours in 2 series 
(Bellmunt and Dutcher 2013, Sweeney et al 2002) and in one study, correlated with higher 
stage tumours (Sweeney et al 2002). 
MET is a transmembrane receptor tyrosine kinase essential for embryonic development and 
wound healing normally activated through interaction with its specific ligand, hepatocyte 
growth factor (HGF).  During tumourigenesis, activation of the MET pathway triggers tumour 
growth, promotes tumour angiogenesis, and induces tumour metastases.  Aberrant MET 
activation in tumour can be achieved by four different ways: (a) MET amplification, (b) MET 
protein overexpression, (c) MET activating mutations and (d) by the formation of an HGF/ 
MET autocrine/paracrine loop.  Mutations in the tyrosine kinase domain of MET have been 
identified in patients with a hereditary form of PRCC, directly implicating MET in human 
tumourigenesis (Schmidt et al 1997, Jeffers et al 1997).  In addition, trisomy of chromosome 7 
(the location of both MET and HGF) is present in a high proportion of patients with PRCC, 
ranging from 40% to 75% of patients, and is thought to be a hallmark of this subtype of RCC 
(Choueiri et al 2013, Klatte et al 2009, Kovacs 1993, Fischer et al 1998).  Evidence supporting 
the validity of MET as a therapeutic target in PRCC patients comes from the results of a 
Phase II study of foretinib (a multikinase inhibitor targeting MET, VEGF, and other receptors) 
in sporadic and hereditary PRCC (N=74) (Choueiri et al 2013).  The ORR was 13.5% in the 

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overall population; however, the presence of germline MET mutations correlated strongly with 
foretinib activity (5 of 10 versus 5 of 57 patients with and without germline MET mutations, 
respectively).  One of five patients with a somatic MET mutation had a Partial Response (PR). 
1.1.3 
Savolitinib/AZD6094 (HMPL-504) 
Savolitinib (also known as AZD6094, HMPL-504 or volitinib) is a potent and selective ATP 
competitive, small molecule MET kinase inhibitor, with enzymatic and cellular IC50s of 4 nM 
and <10 nM, respectively.  It potently inhibits MET autophosphorylation and cell functions 
related to MET phosphorylation such as HGF-dependent or -independent tumour cell 
proliferation.  Consistent with its potent enzyme and cell activity, savolitinib was found to 
inhibit cell growth in vitro in tumours with MET amplification in the absence of HGF-
stimulation with IC50s generally below 10 nM.  It also potently inhibited HGF-stimulated cell 
proliferation in tumours with MET overexpression or carrying a HGF/MET autocrine loop.  In 
human xenograft models in the mouse, savolitinib demonstrated antitumour activity against 
MET-amplified gastric and lung tumours with the median effective dose (ED50) below 
5 mg/kg following QD oral treatment. 
1.1.3.1 
Pharmacokinetics 
The data collected following single dosing in the first-time-in-human (FTIH) study suggest 
that savolitinib is rapidly absorbed at all doses with the geometric mean (minimum-maximum) 
time to reach maximum concentration (tmax) ranging from 1 hour to 3 hours (0.5 to 6.2) across 
all regimens.  Savolitinib was absorbed PO with high exposures.  The t1/2 ranged from 
3.6 hours to 6.8 hours.  Data from the food effect study in normal volunteers suggest that the 
major route of clearance for savolitinib is likely to be metabolism. 
1.1.3.2 
Pharmacology and safety 
 
 
 
 
 
 
 
 
 
1.1.3.3 
Clinical antitumour activity data in patients with PRCC 
Preliminary evidence of clinical activity and biomarker data collected in the FTIH 
dose-escalation savolitinib study demonstrated that patients with PRCC and MET copy 
number gains via amplification or chromosome 7 gain may benefit from single-agent 

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treatment with savolitinib (Gan et al 2015). Of the 8 PRCC patients in the FTIH study treated 
at various doses and schedules, five harboured MET copy number gains by one of these 
mechanisms.  Of these 5 patients, 3 patients (2 treated at 600 mg QD and 1 at 1000 mg QD) 
are partial responders, and a fourth received benefit as evidenced by a 25% decrease change in 
tumour measurements from baseline.  Of the 3 partial responders, 1 patient with MET focal 
amplification remained in the study for 72 weeks, two patients with chromosome 7 gain 
remained on savolitinib for 39 and 147 weeks respectively.  Of note, the PRCC patients that 
did not have MET alterations did not respond to treatment.  
In the Phase II PRCC study (clinicaltrials.gov identifier: NCT02127710), archival tumour 
samples were mandated for exploratory biomarker analysis.  As of November 2016, ninety of 
the 109 enrolled patients had sufficient tumour submitted for analysis of MET status and of 
these, 44 patients were found to have tumours that are MET-driven (ie, chromosome 7 gain, 
MET focal amplification, MET kinase domain mutations, HGF amplification, or any 
combination of these alterations) and 46 patients have MET-negative tumours. All patients 
have had 12 months of follow-up.  
An ORR of 18.4% (8/44 patients) has been observed in the patients with MET-driven disease; 
no PR or CR were observed in the 46 MET-negative and 19 MET-unknown patients.  The 
median PFS (and 95% confidence interval) was 24.7 weeks (17.7, 35.4), 6.4 weeks (6.1, 11.9) 
and 12.1 weeks (6.1, 33.6) in the MET-positive, MET-negative and MET-unknown patients, 
respectively (p=0.0003).  Median PFS is 24.7 weeks in the patients with MET-driven tumours 
compared with 6.4 weeks in the patients with MET-negative tumours.  
Based on this data set, a validated NGS assay which can detect chromosome 7 gain, MET 
amplification, MET kinase domain mutations, and HGF amplification will be used to 
prospectively determine eligibility for this trial. 
1.1.3.4 
Clinical monotherapy safety data 
Savolitinib has been administered at various doses ranging from 100 mg to 1000 mg per day.  
As of January 2016, an estimated 233 patients had received at least 1 dose of savolitinib as 
monotherapy.  To date, the majority of patients have received monotherapy savolitinib at 
500 mg BID (60 patients) and 600 mg QD (125 patients).   
Eighty-five percent (198/233) of patients had an AE that was considered by the investigator to 
be related to savolitinib treatment. The most frequently reported causally related AEs (≥5% of 
patients overall) were nausea (97/233 patients, 41.6%), vomiting (56/233 patients, 24.0%), 
fatigue (49/233 patients, 21.0%), peripheral oedema (34/233 patients, 14.6%), decreased 
appetite (29/233 patients, 12.4%), diarrhoea (23/233 patients, 9.9%), blood creatinine 
increased (20/233 patients, 8.6%), ALT increased (19/233 patients, 8.2%), AST increased 
(19/233 patients, 8.2%), and constipation (12/233 patients, 5.2%). 

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Causally related SAEs reported in more than 1 patient were: increased ALT and abnormal 
hepatic function (each reported in 4 patients); increased ALT and liver injury (each reported in 
3 patients); and increased AST, drug-induced liver injury, and pyrexia (each reported in 
2 patients).  See section 6.1.1 for AEs of special interest for savolitinib. 
1.2 
Rationale for study design, doses and control groups 
1.2.1 
Research hypothesis  
The research hypothesis is that savolitinib monotherapy will be more effective than sunitinib 
monotherapy in patients with MET-driven, unresectable and locally advanced, or metastatic 
papillary renal cell carcinoma (PRCC), as assessed by BICR-confirmed progression-free 
survival (PFS). 
1.2.2 
Rationale for Savolitinib in PRCC 
This is a Phase III study comparing savolitinib to sunitinib in patients with unresectable and 
locally advanced, or metastatic PRCC, with or without previous treatment. This trial is 
justified for the following reasons: 
 
The relevance of altered MET signalling in RCC and in particular in PRCC has been 
established.  For PRCC, NGS has been able to identify patients with MET abnormalities 
that can be important drivers of the disease, eg, chromosome 7 gain is present in 
approximately 40% to 75% of patients with PRCC. Preclinical studies have shown that 
activation of MET signalling promotes angiogenesis and may play a role in adaptive 
resistance to VEGF blockade.  
 
Savolitinib monotherapy is capable of inhibiting tumour growth in mouse tumour models 
harbouring MET aberrations in multiple indications. 
 
A Phase II study of savolitinib has shown preliminary clinical efficacy in patients with 
MET-driven PRCC.  With a short follow-up, approximately 20% of MET-driven patients 
have shown an objective response at 6 months.  
 
Based on data from Phase I and II studies, the administration of savolitinib 600 mg/day is 
generally well tolerated with the majority of events being low grade and with a low 
incidence of treatment-related withdrawals.  As outlined in Section 6.1.1, patients with 
lower body weights may be at greater risk of hepatotoxicity.  Therefore, a 400-mg dose 
for patients below 50 kg will be used to potentially reduce the risk of hepatotoxicity. 
 
In summary, early evidence of antitumour activity, tolerability, and a clear molecular rationale 
warrant a Phase III trial of savolitinib to confirm efficacy in a comparative study. 
1.2.3 
Rationale for sunitinib as comparator 
Sunitinib is a multi-kinase VEGF inhibitor approved by the Food and Drug Administration for 
the treatment of advanced renal-cell carcinoma and is considered a first-line treatment option. 
The biology of VEGF expression as a result of VHL mutation applies exclusively to clear-cell 

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RCC, and thus the most robust effects of VEGF-targeting agents are expected in patients with 
pure clear-cell histology.  To date, there are no proven treatments approved specifically for 
non-clear cell RCC although Phase II studies have shown responses to VEGF TKIs.  
Two recent randomised studies in non-clear cell RCC (Armstrong et al 2016, Tannir et al 
2015) showed a trend towards better disease control with sunitinib than with everolimus.  In 
the ASPEN study, sunitinib significantly increased PFS compared with everolimus (8.3 
months [80% CI 5.8–11.4] vs 5.6 months [5.5–6.0]; hazard ratio 1.41 [80% CI 1.03–1.92]; 
p=0.16), although heterogeneity of the treatment effect was noted on the basis of histological 
subtypes and prognostic risk groups.  Additionally, in an exploratory, non-powered subset 
analysis of the ASPEN trial, sunitinib was more effective in prolonging PFS in patients with 
PRCC (66% of the patient population) than everolimus (8.1 months [80% CI 5.8-11.1] for 
sunitinib vs. 5.5 months [4.4-5.6] for everolimus).   
1.2.4 
Rationale for line-agnostic study 
Preliminary analysis of the Phase II PRCC study suggests that the main determinant of benefit 
from savolitinib is MET-driven status.  The updated Phase II study data from November 2016 
show no apparent difference in PFS between MET-driven first-line patients (N=21) and 
MET-driven patients who were previously treated (N=23), supporting the line-agnostic 
design. 
1.2.5 
Rationale for exclusion of patients with co-occurring FH/VHL 
mutations  
Molecular characterisation of PRCC by The Cancer Genome Atlas (TCGA) Research 
Network (The Cancer Genome Atlas Research Network 2016) has classified PRCC into three 
molecular subgroups independent of histology.  One such group described a CpG island 
methylator phenotype (CIMP) subtype which was described in 5.6% of PRCC cases.  The 
CIMP subtype is characterised by a mutation of the gene encoding fumarate hydratase (FH). 
These tumours were associated with the worst overall survival (OS). Germline mutation of FH 
has been observed in the aggressive type 2 tumours associated with the hereditary 
leiomyomatosis and renal-cell cancer syndrome (Grubb et al 2007).  It is not known whether 
alterations of FH or the MET pathway will be the dominant driver in the <6% of PRCC that 
may harbour both of these pathway alterations. 
In the Phase II savolitinib study (clinicaltrials.gov identifier: NCT02127710), no patient with 
MET-driven PRCC and a co-occurring FH mutation experienced clinical benefit from drug 
treatment.  Therefore, the Phase III savolitinib study will exclude patients with co-occurring 
FH- and MET-driven status. 
Von Hippel-Lindau (VHL) mutation is the hallmark of clear cell renal carcinoma, present in 
nearly 90% of sporadic clear cell kidney cancers (Linehan et al 2012).  Several FDA-approved 

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agents that target the VHL pathway, including sunitinib, have been approved for the treatment 
of patients with advanced kidney cancer.  No patient with MET-driven PRCC in the Phase II 
savolitinib study was found to have a co-occurring VHL mutation.  Therefore, the Phase III 
study will exclude patients with co-occurring VHL and MET-driven status. 
1.3 
Benefit/risk and ethical assessment 
Patients with locally advanced or metastatic PRCC have no curative or standard of care 
treatment options.  Standard therapies used to manage patients with renal cell cancer appear to 
be less effective in patients with PRCC compared to those with clear cell RCC.  Aberrant 
MET activation is prominent in PRCC as a result of MET amplification, HGF/MET protein 
overexpression, MET activating mutation or HGF/MET autocrine loops.  In addition, trisomy 
of chromosome 7 (locus of both MET and its ligand HGF) is present in 40% to 75% of 
patients with PRCC.  The Phase II study showed a significant improvement in PFS in 
MET-driven patients compared to MET-negative patients. No responses have been seen in 
MET-negative patients.  Drug-induced liver injury (DILI) has been identified as a risk for 
patients receiving savolitinib and requires specific monitoring.  Frequent monitoring of liver 
function tests will take place as outlined in the study plan.  The hepatotoxicity management 
algorithm included in the protocol clearly defines and limits the patients who can be 
re-challenged to those with lower grade abnormalities with rapid resolution.  As stated in the 
eligibility criteria and risk mitigation sections, patients with abnormal baseline liver function 
tests will be excluded from the study and patients will be required to discontinue or reduce the 
dose of statins prior to study entry.  Pyrexia and hypersensitivity have been identified as a risk 
for patients receiving savolitinib.  Pyrexia was followed in some cases by drug induced liver 
injury (see above) or an association of symptoms suggestive of hypersensitivity such as, but 
not limited to, allergic rash, cytopenia, myalgia/arthralgia 
 
  Patients who experience pyrexia with or without an association of the above 
symptoms after initiation of savolitinib treatment must follow the toxicity management 
guidelines. The QTc interval prolongation potential of savolitinib 600mg was assessed in a 
thorough QT study in healthy volunteers. Analysis of the data concluded that it is a positive 
study as the upper two-sided 90% CI for the mean placebo-adjusted change from baseline in 
QTc corrected by Fridericia's method (ΔΔQTcF) was 13.6 and 14.0 msec at 4 and 5 hours, 
respectively. Regular ECG assessments will be done throughout the study according to the 
study plan. Patients who present ECG abnormalities with or without symptoms during 
treatment with savolitinib must follow the QTc prolongation toxicity management guidelines. 
 
The investigation of savolitinib in this patient population appears acceptable based upon the 
non-clinical safety profile, the emerging clinical safety profile, the risk minimisation and 
adverse event management strategies, evidence of activity in patients with MET-driven 
PRCC, the lack of effective alternative treatments and the strength of the scientific hypothesis 

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under evaluation.  Overall the benefit/risk assessment supports the administration of 
savolitinib in patients with MET-driven PRCC in accordance with this protocol. 
1.4 
Study design  
This is an open-label, randomised, controlled, multicentre, phase III study designed to 
evaluate the efficacy of savolitinib compared to sunitinib in patients with MET-driven, 
unresectable and locally advanced, or metastatic PRCC.  Patients can be treatment naïve or 
previously treated but cannot have previously received sunitinib or a MET inhibitor.  Patients 
who have received prior systemic therapy must have had disease progression in soft tissue 
disease or bone within 6 months of the last dose of the most recent systemic therapy.  Bone 
progression is defined by the appearance of ≥2 new lesions on bone scan.  Supportive care 
agents such as denosumab or radium 223 are not considered prior systemic therapy, and 
patients who have received these agents are potentially eligible.   
Patients must have at least one lesion that can be accurately measured at baseline as ≥10 mm 
in the longest diameter (except lymph nodes which must have short axis ≥15 mm) with CT or 
MRI and which is suitable for accurate repeated measurements and Karnofsky Performance 
Status ≥80. 
Once the patient has undergone the Part 1 screening visit and signed the Part 1 ICF, a 
formalin-fixed and paraffin-embedded (FFPE) tumour sample meeting the requirements 
specified in the Laboratory Manual will be sent to the sponsor-designated central 
laboratory.  For first-line patients, the diagnostic specimen can be used.  For previously treated 
patients, the most recent archival specimen obtained during a clinical procedure is preferable 
to the diagnostic specimen only if it meets specifications and has an equal or higher tumour 
cellularity.  If the above is not available or unlikely to yield sufficient material for testing, the 
patient will have the option to provide an FFPE tumour tissue block from a de-novo core 
needle tumour biopsy. The biopsied tumour lesion must not be a RECIST target lesion, as the 
biopsy may affect the accuracy of the imaging.  
Locally available pathology results confirming PRCC will be used for study entry.  All 
patients must have a confirmed MET-driven tumour by the sponsor designated central 
laboratory using Next Generation Sequencing (NGS) to evaluate for qualifying alterations 
prior to study entry. 
A MET-driven tumour is defined as any of the following molecular alterations or combination 
of these alterations detected in tumour tissue using the validated NGS test in the absence of 
co-occurring FH or VHL mutations:   
 
Chromosome 7 gain.  
 
MET amplification. 

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 
MET kinase domain mutations.  
 
HGF amplification. 
Absence of co-occurring VHL mutation in “MET-driven” tumours is also required as VHL 
mutations are a hallmark of ccRCC. 
The main study (Part 2) screening assessments must take place within 28 days of signing the 
ICF for Part 2.  Randomisation must take place within 28 days of signing the ICF for Part 2. 
Patients who fulfil all the eligibility criteria will be randomised in a ratio of 1:1 to receive: 
 
Savolitinib 600 mg (400 mg if <50 kg) by mouth (PO) with a meal once daily (QD) 
versus 
 
Sunitinib 50 mg PO QD, with or w/o food.  
 
For the purposes of planning, a 6-week period will be called a ‘cycle’.  Treatment with 
sunitinib will be given 4 weeks on/2 weeks off.  Treatment with savolitinib will be given 
continuously.  
Patients will be stratified based on the IMDC risk group criteria (Kroeger et al 2013), using 
the number of pre-defined risk factors to assign patients into favourable, intermediate or poor 
prognostic groups as well as whether they are treatment naive or previously treated with or 
without a VEGF-TKI.  
Following randomisation, patients will attend scheduled study visits as outlined in the study 
Plan (Table 1).  Efficacy will be assessed by tumour assessments every 6 weeks, 
corresponding to the start of each cycle, and then every 12 weeks after the first year, until 
disease progression as defined by RECIST 1.1 and confirmed by BICR.  All scans will be read 
by BICR after notification of Progressive Disease by the investigator. If PD is not centrally 
confirmed, each subsequent scan will be read by BICR once it is received and processed by 
the sponsor-designated vendor (see Section 5.1.3).  Depending on the speed and completeness 
of image submission to the sponsor-designated vendor, the turn-around time generally should 
be within 10 days. 
During verification of the institution’s diagnosis of radiographic progression by BICR, 
participants should continue to receive study treatment if not medically contra-indicated.  The 
decision whether to continue or to withhold study treatment will be at the discretion of the 
investigator, but if not medically contra-indicated, patients should be strongly encouraged not 
to start subsequent anti-cancer therapy until BICR-confirmation of PD.  If disease progression 
is not confirmed by BICR, the patient may continue/resume study treatment and must 
continue to undergo assessments as per Table 1, including tumour evaluations at 6-week 
intervals (or sooner if felt to be medically indicated) until disease progression is confirmed by 

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BICR.  Those patients who begin subsequent non-study anti-cancer therapy prior to 
BICR-confirmed PD should continue to undergo tumour assessments, and sites must send 
each scan to the sponsor-designated vendor until PD is confirmed by BICR. 
Regardless of initial treatment, patients will have two options for post-progression therapy 
following BICR-confirmation of PD: 
1 
Receive subsequent non-study anti-cancer therapy that does not contravene local practice. 
2 
Continue to receive the assigned study treatment as long as in the opinion of the 
investigator, the patient is deriving benefit and the patient meets the original eligibility 
criteria in terms of Performance Status and laboratory values.  This decision must be 
discussed with and approved by the AstraZeneca study physician.  Such patients will 
continue to undergo monitoring as per the Study Plan (Table 1). 
 
There will be no cross-over. 
An EOT visit will be conducted as soon as possible and preferably within 7 days following the 
decision to discontinue study medication.  
The purpose of this visit is to:  
(a) discuss any further treatment options and/or follow-up.  
(b) discuss the possibility of a biopsy, which should be strongly encouraged, particularly 
for patients who had responded to treatment (patients may have signed a consent line 
for this on the Main Study ICF). 
(c) obtain the required EOT tests (Table 1) and collect the ePRO device after the last set 
of questionnaires are completed. 
(d) collect any unused study medication and study-medication containers from the 
patient. 
 
Once a patient permanently discontinues study drug, a 30-day (±7 days) safety follow-up will 
be performed to follow-up on any SAE/AEs and concomitant medications (including any 
subsequent cancer therapy).  If there are no ongoing SAE/AEs at the time of drug 
discontinuation, the safety follow-up can be done via telephone contact.   
Determination of PD on subsequent anti-cancer therapy in patients who had PD by RECIST 
1.1 on study medication (PFS2) will be by institutional call.  Patients who choose to continue 
on their initial therapy after BICR-confirmed PD will not be considered to have a second PFS 
event until they discontinue study medication and progress on subsequent anti-cancer 
treatment.   

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In the OS follow-up period following second progression (PFS2), subsequent therapies and 
vital status will be documented at least every 12 weeks until death, lost to follow-up, 
withdrawal of consent, or end of study, whichever comes first. 
A recent review of the final results of the Molecular Epidemiology Study (MES) concluded 
that in this data-set, 
 
 
  It was also concluded that the 
SAVOIR study design would not benefit from a study size reassessment 
 
 
 
Following a review of the MES results, a decision, endorsed by the Independent Data 
Monitoring Committee (IDMC), was made to terminate recruitment into SAVOIR. 
Patients randomised in SAVOIR may continue to receive their assigned treatment for as long 
as they are deriving clinical benefit or until they meet a protocol-defined stopping criterion 
and must follow the study plan as outlined.  Patients already in screening (who have signed 
the ICF) will have the option to continue screening and to be randomised if eligible. 
Further information can be found in Section 4.3.5. 
 

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Figure 1 
Study flowchart 
 
BICR, Blinded Independent Central Review; FH/VHL, fumarate Hydratase/von Hippel-Lindau; PD, progression of disease; PFS2, second progression-free 
survival; PO, orally; PRCC, papillary cell renal carcinoma; QD, once a day. 
 

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1.5 
Study governance and oversight 
1.5.1 
Independent Data Monitoring Committee 
This study will use an external IDMC to perform interim reviews of accumulating study safety 
data.  This committee will be composed of therapeutic area experts, including an independent 
hepatic expert to evaluate potential Hy’s law cases, and a statistician, who are not employed 
by AZ, and do not have any major conflict of interest.  Following the review, the IDMC will 
recommend whether the study should continue unchanged, be terminated, or be modified in 
any way.  Once the IDMC has reached a recommendation, a report will be provided to 
AstraZeneca.  The report will only include the recommendation and any potential protocol 
amendments.  A separate IDMC charter will be developed which will contain details of the 
IDMC members and clearly define the responsibilities of the IDMC.  The charter will describe 
the plan to provide safety reports (individual case safety report or serious adverse event 
report) and follow up safety reports concerning liver dysfunction to the IDMC in real time.  
In addition to the periodic review of safety data by an IDMC, the safety of all AstraZeneca 
clinical studies is closely monitored on an on-going basis by AstraZeneca representatives in 
consultation with the Patient Safety Department.  Issues identified will be addressed; this 
could involve, for instance, amendments to the study protocol and letters to investigators. 
Abnormalities in liver function tests as well as any clinical adverse events associated with 
liver dysfunction will be reported quarterly to the FDA. 
Following IDMC endorsement to terminate recruitment into SAVOIR, the interim analysis 
will not occur.  However, interim reviews of safety data by the IDMC will continue until end 
of study.  Further statistical information can be found in Section 8.1. 

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2. 
STUDY OBJECTIVES 
2.1 
Primary objective 
Primary objective: 
Outcome measure: 
To determine the efficacy of savolitinib when 
compared to sunitinib in patients with 
MET-driven, unresectable and locally advanced, 
or metastatic PRCC  
• 
PFS (time to earliest progression as defined by 
RECIST 1.1 and confirmed by BICR, or death) 
 
2.2 
Secondary objectives 
Secondary objective: 
Outcome measure: 
To compare the efficacy of savolitinib versus 
sunitinib in patients with MET-driven, 
unresectable and locally advanced, or metastatic 
papillary renal cell carcinoma (PRCC)  
• 
Overall Survival (OS) 
• 
Objective Response Rate (ORR), duration of 
response (DoR) and best percentage change in 
tumour size by BICR using RECIST 1.1 criteria   
• 
Disease Control Rate (DCR) at 6 and 12 months 
To assess the impact of savolitinib and sunitinib 
on disease related symptoms and health-related 
QOL in this patient population  
• 
Mean change from baseline in FKSI-19 and 
FACIT-F scores  
 
To evaluate the pharmacokinetics of savolitinib in 
this patient population 
• 
PK concentration data 
 
2.3 
Safety objectives 
 
2.4 
Exploratory objectives   
Exploratory objective: 
Outcome measure: 
To compare the efficacy of savolitinib versus 
sunitinib in patients with MET-driven, 
unresectable and locally advanced, or metastatic 
papillary renal cell carcinoma PRCC 
• 
Time from randomisation to objective disease 
progression on subsequent anti-cancer therapy after 
PD by RECIST 1.1 on study medication, or death 
(PFS2)  
To assess the impact of savolitinib vs. sunitinib on 
patient reported AEs 
• 
Collection of PRO CTCAE symptoms  
Safety objective: 
Outcome measure: 
To evaluate the safety and tolerability of 
savolitinib in relation to sunitinib 
• 
AEs/SAEs adverse events [AEs] as characterised and 
graded by National Cancer Institute [NCI] Common 
Terminology Criteria for Adverse Event [CTCAE], 
collection of clinical chemistry/haematology 
parameters, liver function tests, echocardiograms and 
electrocardiograms (ECGs), vital signs including 
blood pressure (BP) and heart rate  

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Exploratory objective: 
Outcome measure: 
To investigate the health economic impact of 
treatment and the disease on hospital related 
resource use and health state utility 
• 
Number, type and reason for hospitalisations and 
unscheduled clinic visits, procedures undertaken 
and length of hospital inpatient stays  
• 
Health state response and utility index derived from 
the EQ-5D-5L 
 
 
  
 
 
 
 
To collect and store DNA (according to each 
country’s local and ethical procedures) for future 
exploratory research into genes/genetic variation 
that may influence response (ie, distribution, 
safety, tolerability and efficacy) to study 
medications and or susceptibility to disease 
(optional) 
• 
Pharmacogenetic analyses on blood samples  
 
 
 
  
 
The exploratory analyses may not be reported in the clinical study report (CSR).  They may be 
reported separately and may also form part of a pooled analysis with other studies.  
3. 
PATIENT SELECTION, ENROLMENT, RANDOMISATION, 
RESTRICTIONS, DISCONTINUATION AND WITHDRAWAL  
Each patient should meet all of the inclusion criteria and none of the exclusion criteria for this 
study.  Under no circumstances can there be exceptions to this rule. 
The patient population should be selected without bias. Investigator(s) should keep a record of 
the patient screening log for both Part 1 and Part 2.  Determination of MET-driven status at 
any laboratory other than the sponsor-designated central laboratory will not be permitted. 
3.1 
Inclusion criteria 
* After signing the Part 1 ICF, patients will undergo eligibility review of the asterisked criteria 
and after signing the Main Study (Part 2) ICF, patients will undergo eligibility review of all 
inclusion/exclusion criteria below.   
For inclusion in the study patients should fulfil the following criteria: 
1 
Provision of informed consent prior to any study specific procedures, sampling and 
analyses.* 
2 
Females and/or males age ≥18 years.* 

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3 
Histologically confirmed PRCC, which is unresectable and locally advanced, or 
metastatic*. Patients with minor clear cell components (<50%) are permitted, provided 
that the dominant and presumed primary histology is papillary.  Patients with papillary 
urothelial carcinoma or renal pelvis cancer of the kidney are not considered PRCC and 
are not eligible.  
4 
Patients who have received no prior systemic therapy as well as those who have received 
prior systemic therapy for PRCC in the advanced setting.* Patients can be treatment-
naïve, or previously treated, but cannot have previously received sunitinib or a MET 
inhibitor.  Patients who have received prior systemic therapy must have had disease 
progression in soft tissue disease or bone within 6 months of the last dose of the most 
recent systemic therapy.  See Section 1.4. 
5 
Confirmation of MET-driven PRCC without co-occurring FH or VHL mutations from an 
FFPE tumour sample using the sponsor-designated central laboratory validated NGS 
assay. 
6 
Karnofsky performance status ≥80.  
7 
Patients must have measurable disease on the baseline scan as per RECIST 1.1 (see 
Appendix F). The main target lesion should preferably not have been used for a biopsy 
within 4 weeks of randomisation. 
8 
Adequate haematological function, defined as: 
 
Absolute neutrophil count (ANC) ≥1500/μL 
 
Haemoglobin (Hgb) ≥9 g/dL (no transfusion in the past 2 weeks) 
 
Platelets ≥100,000/µL (no transfusion in the past 10 days) 
9 
Adequate liver function defined as: 
 
ALT and AST ≤2.5 x the upper limit of normal (ULN) with total bilirubin (TBL) ≤1x 
ULN 
OR 
 
TBL >1xULN-≤1.5x ULN with ALT and AST ≤1x ULN  
10 Adequate renal function defined as a creatinine <2 times the institutional upper limit of 
normal OR a glomerular filtration rate (GFR) ≥30 mL/min, as assessed using the standard 
methodology at the investigating centre (eg, Cockcroft-Gault, MDRD or CKD-EPI 
formulae, EDTA clearance or 24-hour urine collection). 
11 Adequate coagulation parameters defined as International Normalisation Ratio (INR) and 
activated partial thromboplastin time (aPTT) <1.5 x ULN, unless patients are receiving 
therapeutic anti-coagulation which affects these parameters.   
12 Adequate cardiac function defined as an ejection fraction (EF) of ≥50%.  
13 Patients with known tumour thrombus or deep vein thrombosis (DVT) are eligible if 
clinically stable on anticoagulation for ≥2 weeks. 
14 Females should be using adequate contraceptive measures, should not be breast feeding, 
and must have a negative pregnancy test if of childbearing potential, or must have 
evidence of non-childbearing potential by fulfilling one of the following criteria: 

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 
Post-menopausal defined as aged more than 50 years and amenorrhoeic for at least 
12 months following cessation of all exogenous hormonal treatments 
 
Documentation of irreversible surgical sterilisation by hysterectomy, bilateral 
oophorectomy or bilateral salpingectomy but not tubal ligation. 
 
Women under the age of 50 years would be considered postmenopausal if they have 
been amenorrhoeic for 12 months or more following cessation of exogenous 
hormonal treatments and with LH and FSH levels in the post-menopausal range for 
the institution.   
15 Male patients with female partners of child-bearing potential should be willing to use 
barrier contraception, ie, condoms, during the study and for 6 months following 
discontinuation of study drug. 
16 Ability to swallow and retain oral medications. 
17 Willingness and ability to comply with study and follow-up procedures*. 
 
3.2 
Exclusion criteria 
Patients should not enter the study if any of the following exclusion criteria are fulfilled: 
1 
Involvement in the planning and/or conduct of the study (applies to both AstraZeneca 
staff and/or staff at the study site)*. 
2 
Previous randomisation on the present study*. 
3 
Most recent cytotoxic chemotherapy, immunotherapy, chemo-immunotherapy, or 
investigational agents <28 days from the date of randomisation.  Most recent 
non-cytotoxic targeted therapy <14 days from the date of randomisation. 
4 
Unresolved toxicities from any prior therapy greater than Common Terminology Criteria 
for Adverse Events (CTCAE) Grade 1 on the date of randomisation with the exception of 
alopecia. 
5 
Prior treatment with a MET inhibitor (eg, foretinib, crizotinib, cabozantinib, onartuzumab 
or previous savolitinib) or sunitinib.* 
6 
Treatment with strong inducers or inhibitors of CYP3A4 or strong inhibitors of CYP1A2, 
taken within 2 weeks or not possible to be stopped for at least 2 weeks before the date of 
randomisation.  Herbal medications cannot be taken within 7 days of the date of 
randomisation (3 weeks for St John’s wort). See Appendix H.  
7 
Wide field radiotherapy (including therapeutic radioisotopes such as strontium 89) 
administered ≤28 days or limited field radiation for palliation ≤7 days prior to the date of 
randomisation or has not recovered from side effects of such therapy. 
8 
Major surgical procedures ≤28 days of randomisation or minor surgical procedures 
≤7 days.  No waiting is required following port-a-cath placement. 
9 
Untreated brain metastases or if treated, radiation or surgery must have been completed at 
least 2 weeks prior to the main study screening visit, without evidence of central nervous 
system disease progression, patients must be neurologically stable with no more than mild 
neurologic symptoms, and without requirement for chronic corticosteroid therapy to 
control symptoms.   

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10 Current leptomeningeal metastases or spinal cord compression due to disease*. 
11 History of serious liver disease, with or without normal LFTs, such as cirrhosis, Wilson’s 
disease*.  
12 Active hepatitis B (positive HBV surface antigen (HBsAg) result) or hepatitis C 
(HCV). Patients with a past or resolved HBV infection are eligible* if: 
 
negative for HBsAg and positive for hepatitis B core antibody [anti-HBc] or  
 
positive for HBsAg but for >6 months have had normal transaminases and HBV 
DNA levels between 0 – 2000 IU/ml (inactive carrier state) and willing to start and 
maintain antiviral treatment for at least the duration of the study 
 
HBV DNA levels >2000 IU/ml but on prophylactic antiviral treatment for the prior 
3 months and will maintain the antiviral treatment during the study 
Patients with positive HCV antibody are eligible only if the qualitative polymerase chain 
reaction test is negative for HCV RNA. 
13 Acute or chronic non-diabetic pancreatic insufficiency or inflammation*. 
14 Active gastrointestinal disease or other condition that will interfere significantly with the 
absorption, distribution, metabolism, or excretion of oral therapy (eg, ulcerative disease, 
uncontrolled nausea, vomiting, diarrhoea Grade ≥2, and malabsorption syndrome).   
15 Uncontrolled hypertension (BP ≥150/95 mmHg despite medical therapy).  
16 Any clinically important abnormalities in rhythm, conduction or morphology of resting 
electrocardiograms (ECGs), including but not limited to complete left bundle branch 
block, third degree heart block, second degree heart block, PR interval >250 msec. 
17 Mean resting QTcF >470 msec for women and >450 msec for men on the Part 2 
screening triplicate ECGs or factors that may increase the risk of QTcF prolongation such 
as chronic hypokalaemia not correctable with supplements, congenital or familial long 
QT syndrome, or family history of unexplained sudden death under 40 years of age in 
first-degree relatives or any concomitant medication known to prolong the QT interval 
and cause Torsades de Pointes (Appendix I). 
18 Any of the following cardiac diseases within the last 6 months: 
 
Unstable angina pectoris 
 
Congestive heart failure (New York Heart Association [NYHA] ≥ Grade 2 
(Appendix K) 
 
Acute myocardial infarction 
 
Stroke or transient ischemic attack  
19 Serious underlying medical condition at the time of treatment that would impair the 
ability of the patient to receive protocol treatment.  
20 Known serious active infection including, but not limited to, tuberculosis, or human 
immunodeficiency virus (positive HIV 1/2 antibodies).  
21 Presence of other active cancers, or history of treatment for invasive cancer, within the 
last 5 years.  Patients with Stage I cancer who have received definitive local treatment at 
least 3 years previously, and are considered unlikely to recur are eligible.  All patients 

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with previously treated in situ carcinoma (ie, non-invasive) are eligible, as are patients 
with history of non-melanoma skin cancer. 
22 Women who are either pregnant or breast-feeding. 
23 Known hypersensitivity to the active or inactive excipients of savolitinib or sunitinib. 
24 Presence of non-healing wounds. 
25 Judgment by the investigator that the patient should not participate in the study if the 
patient is unlikely to comply with study procedures, restrictions and requirements*. 
 
For procedures for withdrawal of incorrectly enrolled patients see Section 3.4. 
3.3 
Patient enrolment and randomisation 
Investigator(s) should keep a record, the subject screening log, of patients who entered Part 1 
screening. 
The investigator(s) will: 
1 
Obtain a signed Part 1 ICF from the potential patient before any study specific procedures 
are performed.  
2 
Assign the potential patient a unique enrolment number, beginning with ‘E#’. 
3 
Determine patient eligibility (please see asterisked criteria in sections 3.1 and 3.2) 
4 
Obtain signed main study (Part 2) ICF from the potential patient before any Part 2 
screening procedures are performed. 
5 
Determine patient eligibility. See Section 3. 
6 
Upon confirmation of eligibility, randomise the patient using the randomisation system 
which is available for this trial, answering all questions which are asked by the system 
including questions relative to the stratification factors. 
7 
The randomisation system will randomly assign treatment (savolitinib or sunitinib) and 
this information will be made available to the site personnel.  
 
If a patient withdraws from participation in the study, then his/her enrolment/randomisation 
code cannot be reused. 
Patient eligibility will be established before treatment randomisation.  Once the eligibility of a 
patient has been confirmed, the investigator (or nominated assistant) should contact the 
IVRS/IWRS Centralised Randomisation Centre for allocation of randomised therapy.  Patients 
will be identified to the Centralised Randomisation Centre using patient E-code and date of 
birth. The actual treatment given to individual patients will be determined by a randomisation 
scheme that has been loaded into the IVRS/IWRS database.  The randomisation scheme will 
be produced by a computer software program called AZRand (AZ Randomisation system) that 
incorporates a standard procedure for generating random numbers. 

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A blocked randomisation will be generated and all centres will use the same list in order to 
minimise any imbalance in the number of patients assigned to each treatment group.  The 
randomisation scheme will be stratified (See Section 3.5) based on: 
 
IMDC risk categorisation (favourable, intermediate, poor prognosis) 
 
Treatment naïve versus previously treated with or without a VEGF-TKI. 
  
Every effort should be made to minimise the time between enrolment and starting treatment. 
3.4 
Procedures for handling incorrectly enrolled or randomised 
patients 
Subjects who fail to meet the eligibility criteria should not, under any circumstances, be 
enrolled or receive study medication.  There can be no exceptions to this rule.  Subjects who 
are enrolled, but subsequently found not to meet all the eligibility criteria must not be 
randomised or initiated on treatment, and must be withdrawn from the study. 
Where a patient does not meet all the eligibility criteria but is randomised in error, or 
incorrectly started on treatment, the investigator should inform the AstraZeneca study 
physician immediately, and a discussion should occur between the AstraZeneca study 
physician and the investigator regarding whether to continue or discontinue the patient from 
treatment.  The AstraZeneca study physician must ensure all decisions are appropriately 
documented. 
3.5 
Methods for assigning treatment groups  
Eligible patients will be randomised in a 1:1 ratio.  The actual treatment given to individual 
patients will be determined by a randomisation scheme that has been loaded into the 
Interactive Voice Response System / Interactive Web Response System (IVRS/IWRS) 
database. 
Patients will be stratified based on the IMDC risk group criteria (Kroeger et al 2013), using 
the number of predefined risk factors to assign patients into favourable, intermediate, or poor 
prognostic groups as well as whether they are treatment naïve versus previously treated with 
or without a VEGF-TKI. The VEGF-TKIs that are currently most used in PRCC treatment 
include sunitinib, bevacizumab, cabozantinib, pazopanib, axitinib, sorafenib, and lenvatinib 
(in combination with everolimus). 
The IMDC model includes the following 6 independent predictors of poor survival at study 
entry: Karnofsky performance status <80%, interval from initial diagnosis to first systemic 
treatment <1 year, haemoglobin <LLN, corrected calcium >ULN, absolute neutrophil count 
>ULN, and platelet count >ULN.  According to the number of poor prognostic factors, 
patients are segregated into favourable (0 factors), intermediate (1 to 2 factors), and poor 

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(≥3 factors) risk groups.  Based on these stratification criteria, patients will be stratified to 1 of 
the following 9 strata: 
 
Treatment naïve, favourable prognosis.  
 
Treatment naïve, intermediate prognosis.  
 
Treatment naïve, poor prognosis.  
 
Previous treatment not including a VEGF TKI, favourable prognosis.  
 
Previous treatment not including a VEGF TKI, intermediate prognosis.  
 
Previous treatment not including a VEGF TKI, poor prognosis.  
 
Previous treatment with a VEGF TKI, favourable prognosis. 
 
Previous treatment with a VEGF TKI, intermediate prognosis.  
 
Previous treatment with a VEGF TKI, poor prognosis.  
 
Specific information concerning the use of IVRS/IWRS will be provided in a separate manual. 
It is recommended that patients commence study treatment on the day of randomisation if 
possible, and if not, then ideally within 3 days. 
3.6 
Restrictions 
3.6.1 
Need for contraception 
There are no studies in pregnant women taking savolitinib or sunitinib.  However, studies in 
animals have shown that either drug may cause harm to a foetus.  Patients of child bearing 
potential and their partners who are sexually active, must agree to the use of highly effective 
forms of contraception while taking study medication.  Female patients on savolitinib must 
continue to use contraception for 1 month after their last dose.  Acceptable methods of 
contraception include full abstinence, tubal ligation, combined oral, transdermal or 
intra-vaginal hormonal contraceptives, medroxyprogesterone injections (eg, Depo-Provera), 
copper-banded intra-uterine devices, hormone impregnated intra-uterine systems, and 
vasectomised partners.  All methods of contraception (with the exception of total abstinence) 
should be used in combination with the use of a condom by their male sexual partner for 
intercourse. 
Studies in animals taking savolitinib have shown some abnormalities in sperm development. 
Therefore, male patients must use a condom during sexual intercourse with a female partner of 
childbearing potential (pregnant or not) and refrain from donating sperm during the study and 
for 6 months after their last dose.  For details refer to Appendix D “Acceptable Birth Control 
Methods”.  

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3.6.2 
Prohibited concomitant medications and treatments 
No other investigational therapy should be given to patients.  No anticancer agents should be 
given to patients other than the study medications.  If such agents are required for a patient, 
then the patient must first be withdrawn from the study. 
Herbal preparations/medicines 
Herbal preparations/medications are not allowed throughout the study.  These herbal 
medications include, but are not limited to St. John’s wort, kava, ephedra (ma huang), gingko 
biloba, dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, and ginseng.  Patients 
should stop using these herbal medications 7 days prior to the date of randomisation (3 weeks 
for St John’s wort). 
Statins 
For patients on savolitinib, discontinuation of statins is advised unless considered essential, in 
which case, the patients should be prescribed the lowest available dose and monitored for the 
effects of increased statin exposure. 
Acetaminophen (Paracetamol) 
The administration of acetaminophen (paracetamol) is restricted to 3 grams per day, or the 
maximum dose approved locally (if less than 3 grams per day) during the study.  In the event 
of an elevation in hepatic transaminases or bilirubin, the use of acetaminophen should be 
avoided until resolution of the affected parameter. 
Drugs that prolong QT interval 
The concomitant administration of drugs known to prolong QT interval is restricted unless 
considered essential due to patient management, in which case, patients should be closely 
monitored with more frequent ECGs. Additional guidance on drugs known to prolong QT 
interval is provided in Appendix I. 
Food restrictions 
Patients should abstain from eating grapefruit and Seville oranges (and other products 
containing these fruits, eg, grapefruit juice or marmalade) during the study.   
UV exposure 
During savolitinib therapy and for 4 weeks after the last dose, patients should be advised to 
avoid prolonged exposure to the sun, wear protective clothing, a hat and seek shade from the 
sun as far as possible; in addition, SPF30+ sunscreen should be used.  Exposure to other 
sources of UV light including sunbeds and tanning booths, etc. should be avoided. 

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3.7 
Post-progression therapy 
Regardless of initial treatment, patients will have two options for post-progression therapy 
following BICR-confirmation of PD: 
1 
Receive subsequent non-study anti-cancer therapy that does not contravene local practice. 
2 
Continue to receive the assigned study treatment as long as in the opinion of the 
investigator, the patient is deriving benefit, and the patient meets the original eligibility 
criteria in terms of performance status and laboratory values.  This decision must be 
discussed with and approved by the AstraZeneca study physician.  Such patients will 
continue to undergo monitoring as per the Study Plan (Table 1) while on study treatment. 
 
There will be no cross-over. 
3.8 
Discontinuation of investigational product 
Patients may be discontinued from savolitinib or sunitinib in the following situations: 
 
Patient decision.  The patient is at any time free to discontinue treatment, without 
prejudice to further treatment. 
 
Adverse Event as per study criteria. 
 
Pregnancy. 
 
Severe non-compliance with the Clinical Study Protocol. 
 
BICR-confirmed PD unless the physician feels that the patient is still deriving benefit 
from the initial treatment and confirms that the patient meets the original eligibility 
criteria in terms of performance status and laboratory values. This must be discussed with 
and approved by the AstraZeneca study physician.   
 
Patients was incorrectly initiated on investigational product (Section 3.4). 
 
The investigator decides the patient should not be continued on the trial/is no longer 
deriving benefit from the study medication. 
 
After discontinuation of the study treatment at any point in the study, all ongoing AEs or 
SAEs must be followed until resolution or until the event becomes stable (or returns to 
baseline) unless, in the investigator’s opinion the condition is unlikely to resolve due to the 
patients underlying disease, or the patient is lost to follow up (see Section 6.3.2).  All new 
AEs and SAEs occurring during the 30 calendar days after the last dose of study treatment 
must be reported (if SAEs, they must be reported to AstraZeneca within 24 hours as described 
in Section 6.4) and followed to resolution or until the event becomes stable (or returns to 
baseline) or is unlikely to resolve further in the opinion of the investigator.  Patients should be 
contacted or seen 30 days (±7 days) after discontinuing the last dose of study medication to 
collect and /or complete AE information.  Any untoward event occurring subsequent to the 
30-day follow-up AE reporting period that the investigator assesses as possibly related to the 
study medication should also be reported as an AE. 

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AstraZeneca retains the right to request additional information for any patient with ongoing 
AE(s)/SAE(s) at the end of the study, if judged necessary. 
Any patient who has not yet shown BICR-confirmed PD at discontinuation of study 
medication should continue to be followed with centrally reviewed scans until there is 
BICR-confirmation of PD, regardless of whether subsequent anti-cancer therapy is started. 
3.8.1 
Procedures for discontinuation of a patient from study treatment prior 
to BICR-confirmed PD  
Patients who discontinue study-medication prior to BICR-confirmed PD will be asked about 
the reason(s) for discontinuation and the presence of any AEs.  In addition, the date of 
discontinuation, the reason and any medications taken at the time of discontinuation will be 
recorded on the eCRF.  If a patient discontinues study treatment, the study monitor must be 
informed immediately.  
If the reason for study medication discontinuation is due to investigator-assessment of PD 
using RECIST 1.1 (but prior to BICR confirmation due to delay or a BICR discrepancy), 
patients should be encouraged, if not medically contraindicated, to not start subsequent 
anti-cancer therapy and continue to undergo disease assessments until BICR-confirmed PD.  
Once there is BICR-confirmed PD, patients will be followed for PFS2 and OS as per 
Sections 4.3.3 and 4.3.4.   
However, if this is not an option for the patient and/or physician, or if the study medication 
was discontinued for any other reason other than PD, then an EOT visit will be conducted as 
soon as possible and preferably within 7 days following the decision to discontinue study 
medication.   
The purpose of this visit for patients who discontinue study-drug prior to BICR-confirmed PD 
is to: 
(a) discuss any additional treatment options and follow-up.  
(b) discuss the possibility of a biopsy, which should be strongly encouraged, particularly 
for patients who had responded to treatment (patients may have signed a consent line 
for this on the Main Study ICF). 
(c) obtain the required EOT tests (Table 1) and collect the ePRO device after the last set 
of questionnaires are completed. 
(d) collect any unused study medication and study-medication containers from the 
patient. 
 
By discontinuing study treatment, the patient is not withdrawn from the study.  If a patient 
decides to voluntarily withdraw (ie, patient choice), then the Withdrawal ICF (Informed 
Consent Form Addendum – Options for Withdrawal of Consent) should be used to determine 

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if they are willing to undergo follow-up.  Section 3.9.2 outlines the criteria for withdrawal 
from study. 
3.9 
Criteria for withdrawal from the study 
Reasons for withdrawal from the study: 
 
Voluntary withdrawal by the patient who is at any time free to discontinue their 
participation in the study without prejudice to further treatment. 
 
Incorrectly enrolled patients ie, the patient does not meet the required inclusion/exclusion 
criteria for the study. This option is only applicable to patients not randomised into the 
study (ie, screen failures identified prior to randomisation). 
 
If a patient voluntarily withdraws consent, they will fill out the Withdrawal ICF (Informed 
Consent Form Addendum – Options for Withdrawal of Consent) and be specifically asked if 
they are withdrawing consent for further follow-up, eg, survival calls. 
3.9.1 
Screen failures  
Screen failures are patients who either are not MET-driven (Part 1 screen failures), and 
therefore cannot go on to the main study (Part 2) screening, or who do not fulfil the eligibility 
criteria for the main study (Part 2 screen failures), and therefore must not be randomised. 
These patients should have the reason for study withdrawal recorded as “Screen failure” (ie, 
the potential patient does not meet one or more of the required inclusion/exclusion criteria) in 
IVRS/IWRS).  ‘Failure to meet randomisation criteria’ should be selected for situations where 
the patient has been unable to fulfil/satisfy the main study (Part 2) criteria required for 
assignment into a randomised group. 
3.9.2 
Withdrawal of the informed consent 
Patients are at any time free to withdraw from the study (study medication and assessments), 
without prejudice to further treatment.  Such patients will always be asked about the reason(s) 
and the presence of any AEs.  If possible, they will be seen and assessed by an investigator. 
Adverse events will be followed up (see Sections 6.3.2 and Section 4.3.2).  All study 
medication and empty study medication bottles should be returned by the patient as well as the 
electronic PRO (ePRO) devices. 
If a patient withdraws from the study, then his/her enrolment/randomisation code cannot be 
reused. 
In the event that the patient has actively withdrawn consent to the processing of their personal 
data, the vital status of the patient can be obtained by site personnel from publicly available 
resources where it is possible to do so under applicable local laws. 

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3.10 
Discontinuation of the study 
The study may be stopped if, in the judgment of AstraZeneca, trial subjects are placed at 
undue risk because of clinically significant findings that: 
 
meet individual stopping criteria or are otherwise considered significant.  
 
are assessed as causally related to study medication.  
 
are not considered to be consistent with continuation of the study. 
 
Regardless of the reason for termination, all data available for the patient at the time of 
discontinuation of follow-up must be recorded in the eCRF.  All reasons for discontinuation of 
treatment must be documented. 
In terminating the study, the Sponsor will ensure that adequate consideration is given to the 
protection of the patients’ interests. 
4. 
STUDY PLAN AND TIMING OF PROCEDURES

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Table 1 
Study schedule: Screening, On Study Treatment, Discontinuation and Follow-up 
 
Part 1 
Screening 
Visit 
Part 2 
Screening 
Visit2 
Cycle 1 
Cycle 2 
Cycle 3 & 
beyond 
(every 6 
weeks) 
EOT18 
Safety 
Follow-
up19  
PFS232 
Overall 
Survival 
Follow-
Up20  
D
1 
D
8 
D
15 
D
22 
D
29 
D
36 
D
1 
D
8 
D
15 
D
22 
D
29 
D
36 
D1 
 
 
 
 
Site Visit 
0 
1 
2 
 
3 
 
4 
 
5 
 
6 
 
 
 
7 
 
 
 
 
Day 
 
-28 to 0 
1 
8 
15 
22 
29 
36 
43 
50 
57 
64 
71 
78 
85 
 
 
 
 
Activity Visit 
Window 
 
 
0 
± 
2d 
± 
2d 
± 
2d 
± 
2d 
± 
2d 
± 
2d 
± 
2d 
± 
2d 
± 
2d 
± 
2d 
± 
2d 
± 
7d 
 
 
 
 
Part 1 Screening 
Informed 
Consent Form1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography, 
medical/surgical 
history3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cancer therapy4 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
FFPE tumour 
sample for MET-
driven status6  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Main Study (Part 
2) Informed 
Consent Form1 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical 
examination  
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
X 
X* 
X27 
 
 
Body weight25 
 
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
Vital signs5  
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
X 
X* 
X27  
 
 

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Table 1 
Study schedule: Screening, On Study Treatment, Discontinuation and Follow-up 
 
Part 1 
Screening 
Visit 
Part 2 
Screening 
Visit2 
Cycle 1 
Cycle 2 
Cycle 3 & 
beyond 
(every 6 
weeks) 
EOT18 
Safety 
Follow-
up19  
PFS232 
Overall 
Survival 
Follow-
Up20  
D
1 
D
8 
D
15 
D
22 
D
29 
D
36 
D
1 
D
8 
D
15 
D
22 
D
29 
D
36 
D1 
 
 
 
 
Site Visit 
0 
1 
2 
 
3 
 
4 
 
5 
 
6 
 
 
 
7 
 
 
 
 
Day 
 
-28 to 0 
1 
8 
15 
22 
29 
36 
43 
50 
57 
64 
71 
78 
85 
 
 
 
 
Activity Visit 
Window 
 
 
0 
± 
2d 
± 
2d 
± 
2d 
± 
2d 
± 
2d 
± 
2d 
± 
2d 
± 
2d 
± 
2d 
± 
2d 
± 
2d 
± 
7d 
 
 
 
 
Tumour 
Assessment16 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
X(by 
institutio
nal call) 
 
Karnofsky 
Performance 
Status 
 
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
X* 
 
 
 
Smoking Status 
(Y/N)24 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Haematology 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
X 
X* 
X27 
 
 
Clinical 
Chemistries29  
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
X 
X* 
X27  
 
 
Corrected 
calcium31 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Liver function 
tests21 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
X 
X* 
X27  
 
 
Hepatitis 
serology30 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Coagulation7  
 
X7 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis8  
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
 
X 
 
X27  
 
 

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Table 1 
Study schedule: Screening, On Study Treatment, Discontinuation and Follow-up 
 
Part 1 
Screening 
Visit 
Part 2 
Screening 
Visit2 
Cycle 1 
Cycle 2 
Cycle 3 & 
beyond 
(every 6 
weeks) 
EOT18 
Safety 
Follow-
up19  
PFS232 
Overall 
Survival 
Follow-
Up20  
D
1 
D
8 
D
15 
D
22 
D
29 
D
36 
D
1 
D
8 
D
15 
D
22 
D
29 
D
36 
D1 
 
 
 
 
Site Visit 
0 
1 
2 
 
3 
 
4 
 
5 
 
6 
 
 
 
7 
 
 
 
 
Day 
 
-28 to 0 
1 
8 
15 
22 
29 
36 
43 
50 
57 
64 
71 
78 
85 
 
 
 
 
Activity Visit 
Window 
 
 
0 
± 
2d 
± 
2d 
± 
2d 
± 
2d 
± 
2d 
± 
2d 
± 
2d 
± 
2d 
± 
2d 
± 
2d 
± 
2d 
± 
7d 
 
 
 
 
Thyroid Function 
tests, LDH 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
Pregnancy test9 
 
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
 
 
 
Triplicate 
ECGs10 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
X 
X 
 
 
 
Echocardio-
gram/MUGA10 
 
X 
 
Every 12 weeks (±2 weeks) relative to first dose 
X 
 
 
 
Prophylactic 
dental exam12 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pharmacogenetic 
sample11 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK blood 
collection13 
 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
 
 
 
 
 
 
 
 
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 

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Table 1 
Study schedule: Screening, On Study Treatment, Discontinuation and Follow-up 
 
Part 1 
Screening 
Visit 
Part 2 
Screening 
Visit2 
Cycle 1 
Cycle 2 
Cycle 3 & 
beyond 
(every 6 
weeks) 
EOT18 
Safety 
Follow-
up19  
PFS232 
Overall 
Survival 
Follow-
Up20  
D
1 
D
8 
D
15 
D
22 
D
29 
D
36 
D
1 
D
8 
D
15 
D
22 
D
29 
D
36 
D1 
 
 
 
 
Site Visit 
0 
1 
2 
 
3 
 
4 
 
5 
 
6 
 
 
 
7 
 
 
 
 
Day 
 
-28 to 0 
1 
8 
15 
22 
29 
36 
43 
50 
57 
64 
71 
78 
85 
 
 
 
 
Activity Visit 
Window 
 
 
0 
± 
2d 
± 
2d 
± 
2d 
± 
2d 
± 
2d 
± 
2d 
± 
2d 
± 
2d 
± 
2d 
± 
2d 
± 
2d 
± 
7d 
 
 
 
 
FACIT-F and 
PRO CTCAE17 
 
 
X 
Bi-Weekly for the first 18 weeks relative to the first dose, then 
every 4 weeks until EOT visit  
X 
 
 
 
EQ-5D-5L and 
FKSI-1917 
 
 
X 
Every 4 weeks until EOT visit 
X 
 
 
 
Hospital 
Resource Use17 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
X 
 
X 
 
 
Concomitant 
Medications 
 
X 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
X 
X 
 
 
 
Adverse Events23 
 
X 
continuously 
X 
 
 
Drug Dispensing/ 
Return33 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
(return 
only) 
 
 
 
IVRS/IWRS 
transactions22 
X 
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
 
 
 
Tumour biopsy at 
relapse28 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 

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1 
Written informed consent must be obtained before any Part 1 or Part 2 screening activities occur. 
2 
Part 2 screening assessments must take place within 28 days of signing the ICF for Part 2. Assessments obtained outside of the 28-day window must be 
repeated before Cycle 1 Day 1. 
3 
Demographic information (age, sex, race, and ethnicity) and a complete medical and surgical history on all (both MET-driven and MET-negative) patients 
will be collected and recorded in the appropriate eCRFs at the Part 1 screening visit. The medical history will include smoking history in pack years 
4 
All previous cancer treatments, including line of therapy, dates of administration, and best response to treatment on all (both MET-driven and 
MET-negative) patients will be collected and recorded in the appropriate eCRF at the Part 1 screening visit. During follow-up, cancer treatments 
administered since discontinuing study treatment will be collected. 
5 
Vital signs include: heart rate, systolic and diastolic blood pressure, height [only at the main study screening] and temperature. 
6 
FFPE tumour sample(s) that meet the specifications in the Laboratory Manual will be analysed prospectively by the sponsor-designated central laboratory 
by NGS for MET-driven status prospectively, or after study entry in cases where a pre-existing “MET-driven” result is available.  See Section 1.4 for 
qualifying MET-driven alterations. 
7 
If INR and aPTT are normal at baseline, they do not need to be repeated unless clinically indicated during the study. Patients on anti-coagulant therapy 
should have coagulation testing performed according to standard management guidelines. 
8 
Urinalysis: If 3+ or greater proteinuria is identified by dipstick assessment, a 24-hour urine collection for formal quantification of the level of protein 
excretion should be performed. 
9 
Women of childbearing potential will have a serum or urine pregnancy test done at main study screening pre-dose Cycle 1 Day 1, on Day 1 of each 
subsequent cycle, and at treatment discontinuation. 
10 
Triplicate ECGs will be performed during the main study (Part 2) screening period, every week in the first cycle, every cycle thereafter, at the end of 
treatment visit if not done within the last 6 weeks, and at other times if clinically indicated. Echocardiogram/MUGAs will be performed during the main 
study (Part 2) screening period, every 12 weeks (±2 weeks) relative to the first dose of study medication, at the end of treatment visit if not done within the 
last 6 weeks, and at other times if clinically indicated.  
11 
A 10-mL blood sample for 
will be obtained from the patient pre-dose on 1 Day 1 (
  If for any 
reason the sample is not drawn prior to dosing it may be collected as soon as possible thereafter.  Only one sample will be collected.  See Section 5.6. 
12 
Patients who have ever received bisphosphonates should undergo a maxillofacial exam during the main study (Part 2) screening period with treatment of 
active infection and prophylactic treatment of any sites that are at high risk for infection. 
13 
Blood sample (2 mL) to be collected from patients assigned to savolitinib pre-dose on Day 1 of Cycle 1, pre-dose and 1 and 3 hours post dosing on Day 15 
of Cycle 1, and pre-dose on Day 29 of Cycle 1 and on Day 57 (ie, Day 15 of Cycle 2). The date/time of the last two doses prior to the pre-dose PK samples 
(should be confirmed in the patient diary) and the date/time the PK sample was drawn and the dose/time the savolitinib is given on the PK day need to be 
recorded in the eCRF. 
14 
 (10 mL whole blood) will be collected at the Part 2 screening visit and pre-dose Cycle 1 Day 1, and on the same day as each tumour 
evaluation (including unscheduled evaluations), corresponding to at least every 6 weeks during the first year and 12 weeks thereafter, and at EOT, 
regardless of whether a sample was just collected at the last scan (see Section 5.7.5). 
15 
A 
(10 mL whole blood) will be collected at the Part 2 screening visit, pre-dose Day 1, Cycle 1, at the time of the first 
tumour evaluation (Cycle 2, Day 1) and at EOT (please see Section 5.7.6). 

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16 
Baseline tumour imaging studies will be performed within 28 days prior to the date of randomisation and will be repeated every 6 weeks (±1 week), 
corresponding to the start of each cycle during the first year and then every 12 weeks (±1 week) thereafter, until BICR-confirmed PD using RECIST 1.1.  
17 
All PRO (FACIT-F, FKSI-19, PROCTCAE and EQ-5D-5L) questionnaires should be completed using the e-PRO device on the schedule above. The site 
should check the PRO data and patient compliance on the web-based portal at every clinic visit. All four questionnaires need to be completed at the EOT 
visit prior to the patient meeting with the physician and then the e-PRO devices should be collected. See section 5.3.2 for hospital resource use, which 
should be completed using the HOSPAD module on a continuous basis until the Safety Follow-up.  
18 
See Section 4.3.1. The asterisked assessments* do not need to be repeated if done within the last 2 weeks and there is no need for follow-up of toxicity.  An 
ECHO/triplicate ECGs need to be performed if not done within the last 6 weeks. 
 and a pregnancy test need to 
be performed. The ePRO device and all unused study medication and study medication bottles should be returned. 
19 
A safety follow-up will be performed 30 (±7) days after discontinuation of study medication, to follow-up on any SAE/AE’s and record any subsequent 
cancer therapy. If there are no ongoing SAE/AEs at the time of drug discontinuation, the safety follow-up can be done via telephone contact. 
20 
All subsequent anti-cancer therapies and OS status will be documented at least every 12 weeks until death, loss to follow-up, withdrawal of consent, or end 
of study, whichever comes first. 
21 
Blood liver functions (AST, ALT, alkaline phosphatase and total bilirubin) will be monitored weekly x 9 and then at the start of each cycle. In some 
situations, blood for LFTs may be drawn at a local lab on the days when there is no scheduled clinic visit although the results must be faxed to the treating 
institution immediately so they can be evaluated in light of the hepatotoxicity algorithm (Section 6.8.1.2 for savolitinib and Section 6.8.2 for sunitinib) and 
entered into the database. 
22 
An IVRS/IWRS transaction needs to be done at every dispensing visit at the start of each cycle. Additionally, every dose reduction needs to be recorded in 
IVRS/IWRS.  
23 
Please see section 6.3. From the part 1 screening visit until the part 2 screening visit, only SAEs related to study procedures must be reported (AEs do not 
require reporting).  From the main study screening (Part 2) onwards, all AEs/SAEs must be reported 
24 
Smoking status (Yes (current smoker) /No (not currently smoking) will be recorded at the time of the main study screening (Part 2) visit. 
25 
Body weight will be assessed every cycle, and more frequently if clinically indicated.  The dose of savolitinib will not change for patients who started the 
study at <50 kg (ie, 400 mg), even if their weight increases to ≥50 kg during the course of the study.   
26 
20 mL for 
at the Part 1 screening visit only (see Section 5.7.4) 
27 
Only necessary if there are ongoing toxicities 
28 
A tumour biopsy after treatment discontinuation should be strongly encouraged regardless of treatment arm, particularly for patients who had responded to 
treatment.  See section 5.7.7.  
29 
See Table 2 (Section 5.2.1) for list of chemistry evaluations 
30 
Hepatitis serology includes HBsAg, anti-HBc (qualitative), HBV DNA, HCV antibody, HCV RNA (if HCV antibody is positive) 
31 
To be used for determination of IMDC risk category. Corrected calcium = total calcium (mg/dL) − 0.707 [albumin (g/dL) − 3.4] 
32 
Patients will enter the PFS2 follow-up period once the patient has discontinued study medication due to PD by RECIST 1.1.  Patients will be followed at 
least every 12 weeks by site personnel for second progression on subsequent anti-cancer therapy and documentation of all subsequent therapy. 

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33 
The number of remaining pills at the end of each cycle should be recorded in RAVE.  Additionally, patients must bring their medication bottles or blister 
packs and all remaining tablets or capsules to each clinic visit so that a medication count and reconciliation can be done in conjunction with the medication 
diary as well as to ensure that the patient has sufficient medication remaining until the next visit. The results of the medication counts and reconciliation 
should be recorded on IP Accountability logs.   

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4.1 
Screening/enrolment period 
Patients will be required to sign a written Part 1 screening ICF for prospective analysis of the 
MET-driven status using a tumour sample by SAVOIR Clinical Trial NGS assay performed in 
sponsor designated central laboratory.  If this tumour analysis, or a pre-existing MET-driven 
commercial NGS assay result from the same laboratory, shows that the tumour is 
MET-driven, patients will be asked to provide informed consent for the main study (Part 2 
ICF) prior to starting any additional screening procedures.  At the Part 1 screening visit, each 
potential patient is assigned a unique enrolment code. If a patient withdraws from the study, 
then the enrolment code cannot be reused. 
A pre-existing MET-driven result from a commercial assay from the sponsor designated 
central laboratory can be used to trigger patient informed consent and entry into the main 
study, if available.  However, a tumour sample from all patients is required for central 
confirmation of MET-driven tumour status using the SAVOIR Clinical Trial NGS assay. 
Demographic data and other characteristics will be recorded and will include: age, gender, 
race and ethnicity according to local regulations. 
A complete medical, surgical and prior anticancer therapy history will be obtained during 
screening. The medical history is to include smoking history in pack-years.  The prior 
anticancer therapy history is to include all previous treatments (eg, targeted therapy, 
immunotherapy, cytotoxic chemotherapy, non-TKI anti-angiogenic therapy or combination 
therapies), line of therapy for each drug or combination, start and stop dates of administration, 
best response to treatment and reason for discontinuing each drug.  
Each patient will undergo the appropriate screening studies as per the study plan (Table 1), 
either during the Part 1 screening period or to confirm eligibility for the main study during the 
Part 2 screening within 28 days of signing the ICF for Part 2 (see Sections 3.1 and 3.2).  
Tumour assessments and other clinical data obtained as standard of care prior to consent may 
be used for the study provided the assessments fall within the protocol specified period prior 
to the date of randomisation. 
4.2 
Treatment period 
Evaluations during the treatment period will be performed as detailed in the Study Plan 
(Table 1). 
4.3 
Post study-drug follow up 
4.3.1 
End of Treatment (EOT) 
An EOT visit will be conducted as soon as possible and preferably within 7 days following the 
decision to discontinue study medication. 

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The purpose of this visit is to: 
(a) discuss any further treatment options and/or follow-up.  
(b) discuss the possibility of a biopsy, which should be strongly encouraged, particularly 
for patients who had responded to treatment (patients may have signed a consent line 
for this on the Main Study ICF). 
(c) obtain the required EOT tests (Table 1) and collect the ePRO device after the last set 
of questionnaires are completed. 
(d) collect any unused study medication and study medication containers from the 
patient. 
 
Standard laboratory tests, physical exam, vital signs and Karnofsky Performance Status do not 
need to be repeated if done within the last two weeks.  An ECHO/MUGA and triplicate ECGs 
need to be performed if not done within the last 6 weeks. Blood for 
 
 and a pregnancy test need to be performed at the EOT visit.  The ePRO device as well 
as any remaining study medication and study medication containers should be returned. 
4.3.2 
Safety follow-up  
If there are no ongoing SAE/AEs at the time of study medication discontinuation, the safety 
follow-up with the patient 30 (±7) days after discontinuation of study medication can be done 
through telephone contact, capturing any new SAEs/AEs and concomitant meds including 
new therapy.  The primary purpose is to follow-up any AEs ongoing at the time of 
discontinuation and to assess any new AEs that may have occurred since discontinuation.  
Any AE/ SAE/ abnormal laboratory findings that are ongoing at the time of study treatment 
discontinuation or any new treatment related events within 30 days of the last study treatment 
must be followed up to resolution or until the event becomes stable (or returns to baseline) or 
is unlikely to resolve further in the opinion of the investigator.   
AstraZeneca retains the right to request additional information for any patient with ongoing 
AE(s)/SAE(s) at the end of the study, if judged necessary. 
4.3.3 
Follow-up for second progression on subsequent anti-cancer therapy 
after PD by RECIST 1.1 (PFS2) 
Following discontinuation of study medication for PD by RECIST 1.1 as determined by 
investigator assessment, patients that started on subsequent therapy post-progression will 
continue to be followed at least every 12 weeks by investigator assessment for documentation 
of second progression.  Subsequent therapy and OS will also be collected.  Determination of 
PD for PFS2 will be by institutional call only.  Patients who choose to continue on study 
therapy after the investigator confirmed PD will not be considered to have a second PFS-event 
until they have discontinued study medication and started subsequent anti-cancer therapy. 

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4.3.4 
Overall survival follow-up 
The OS period begins following determination of PFS2 by institutional call.  In the OS 
follow-up period, all subsequent anti-cancer therapies will be documented by site personnel at 
least every 12 weeks until death, lost to follow-up, withdrawal of consent, or end of study, 
whichever comes first.  
The status of ongoing, withdrawn (from the study) and “lost to follow-up” patients at the time 
of an OS analysis should be obtained by the site personnel by checking the patient’s notes, 
hospital records, contacting the patient’s general practitioner and checking publicly available 
death registries.  In the event that the patient has actively withdrawn consent to the processing 
of their personal data, the vital status of the patient can be obtained by site personnel from 
publicly available resources, where it is possible to do so under applicable local laws.  Sites 
have 5 days following the DCO for the final survival analyses to contact patients and provide 
complete survival data. 
4.3.5 
Patient management post-final analysis 
Stopping criteria for the final analysis are defined in Section 9.3. 
Patients receiving study drug, either savolitinib or sunitinib, will be allowed to remain on 
treatment for as long as they are deriving clinical benefit, in the opinion of investigator(s) or 
until meeting any discontinuation criteria defined in Section 3.8. 
Patients will be monitored in accordance with the investigator’s standard clinical practice and 
national product label (for patients being treated with sunitinib).  Dispensing of study 
treatment post-final analysis will be done outside of IVRS/IWRS.  At routine clinic visits, 
patients will return partially used and unused medication, and a thorough drug accountability 
assessment will be performed at the site. 
AstraZeneca will collect information (during the treatment period and for 30 (±7) days after 
discontinuation of study medication) on SAEs, overdose and pregnancy (as per Section 6.3) 
via paper and emailed (preferably) or faxed directly to Tata Consultancy Services Data Entry 
Site (DES) (also known as AZ DES).  Drug accountability information will be recorded in the 
source documents. 
If an investigator learns of any SAEs, including death, at any time after a patient has 
completed the study, and he/she considers there is a reasonable possibility that the event is 
causally related to the investigational product, the investigator should notify AstraZeneca 
Patient Safety.  Additionally, as stated in Section 6.3, any SAE or non-serious AE that is 
ongoing at the time of this data cut-off, must be followed up to resolution unless the event is 
considered by the investigator to be unlikely to resolve, or the patient is lost to follow-up. 

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5. 
STUDY ASSESSMENTS 
The Web Based Data Capture (WBDC) system will be used for data collection and query 
handling.  The investigator will ensure that data are recorded on the electronic Case Report 
Forms as specified in the Clinical Study Protocol and in accordance with the instructions 
provided. 
The investigator ensures the accuracy, completeness and timeliness of the data recorded and 
of the provision of answers to data queries according to the Clinical Study Agreement.  The 
investigator will sign the completed electronic Case Report Forms.  A copy of the completed 
electronic Case Report Forms will be archived at the study site. 
5.1 
Efficacy assessments 
5.1.1 
Tumour assessments by CT or MRI scans (RECIST 1.1) 
The baseline assessment will be performed no more than 28 days prior to the date of 
randomisation and as close as possible to the start of study treatment.  Following the baseline 
assessment, subsequent tumour assessments should be performed every 6 weeks at the start of 
each cycle (±7 days) during the first year and then every 12 weeks (±1 week) thereafter up to 
the time of BICR-confirmed PD.  Anonymised copies of all CT/MRI scans done for tumour 
evaluation will be sent to an AstraZeneca appointed Contract Research Organisation (CRO) 
for blinded independent central review as soon as possible following completion of each scan 
(see Section 5.1.2).  All scans should be evaluated using RECIST assessments until 
BICR-confirmed progressive disease.  
At baseline, the imaging modalities used for RECIST assessment will be contrast-enhanced 
CT (MRI where CT is contraindicated) scans of the chest, abdomen and pelvis with other 
regions as clinically indicated for the assessment of disease.  The same imaging modality 
should be use for subsequent follow-up assessments and will cover chest (in those patients 
with disease in the chest or upper abdomen lymphadenopathy at baseline), abdomen and 
pelvis with any other regions imaged at baseline where disease was present.  Any other sites 
where new disease is suspected should also be appropriately imaged.   
Radiological examinations performed in the conduct of this study should be retained at the site 
as source data. 
It is important to follow the assessment schedule as closely as possible.  If scans are 
performed outside of the scheduled visit ±7-day window interval and the patient has not 
progressed, every attempt should be made to perform the subsequent scans at their scheduled 
time points. This schedule is to be followed in order to minimise any unintentional bias caused 
by some patients being assessed at a different frequency than others. 

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5.1.2 
Tumour evaluation 
RECIST 1.1 criteria will be used to assess patient response to treatment by determining 
progression free survival (PFS) times, objective response rates (ORR) and duration of 
response (DoR) and disease control rate (DCR).  The RECIST 1.1 guidelines for measurable, 
non-measurable, target and non-target lesions and the objective tumour response criteria 
(complete response, partial response, stable disease or progression of disease) are presented in 
Appendix F. 
Categorisation of objective tumour response assessment will be based on the RECIST 1.1 
criteria of response: complete response (CR), partial response (PR), stable disease (SD), 
progression of disease (PD), and not evaluable (NE). Target lesion (TL) progression will be 
calculated in comparison to when the tumour burden was at a minimum (ie, smallest sum of 
diameters previously recorded on study).  In the absence of progression, tumour response (CR, 
PR, SD or NE) will be calculated in comparison to the baseline tumour measurements 
obtained prior to randomisation. 
If the investigator is in doubt as to whether progression has occurred, particularly with 
response to NTL (non-target lesion) or the appearance of a new lesion, it is advisable to 
continue treatment until the next scheduled assessment or sooner if clinically indicated and 
reassess the patient’s status.  If repeat scans confirm progression, then the date of the initial 
scan should be declared as the date of progression. 
To achieve ‘unequivocal progression’ on the basis of non-target disease, there must be an 
overall level of substantial worsening in non-target disease such that, even in presence of SD 
or PR in target disease, the overall tumour burden has increased sufficiently to merit 
discontinuation of therapy.  A modest ‘increase’ in the size of one or more non-target lesions 
is usually not sufficient to qualify for unequivocal progression status. 
5.1.3 
Central reading of scans/BICR 
An independent review of all scans used in the assessment of tumours using RECIST 1.1 will 
be conducted.  All imaging assessments including unscheduled scans will be collected on an 
ongoing basis and sent to an AstraZeneca appointed CRO following completion of each scan. 
All scans will be read by BICR after notification of Progressive Disease by the investigator.  If 
PD is not centrally confirmed, each subsequent scan will be read by BICR once it is received 
and processed by the CRO.  
Every effort should be made by the institution to send each scan to the CRO as quickly as 
possible, so that Quality Control can be performed and the scans will be ready for review by 
the radiologists at the time that the patient develops Progressive Disease by institutional call.  
This scan, in particular, should be sent to the designated vendor without delay after 
acquisition, to minimise the turn-around time for confirmation of PD by BICR. Depending on 

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the speed and completeness of image submission to the sponsor-designated vendor, the 
turn- around time should generally be within 10 days.   
During verification of the institution’s diagnosis of radiographic progression by BICR, 
participants may continue to receive study treatment.  The decision whether to continue or to 
withhold study treatment will be at the discretion of the investigator, but if not medically 
contra-indicated, patients should be encouraged to not start alternative anti-cancer therapy 
until confirmation of PD by BICR.  If PD is not confirmed by BICR, the patient may 
continue/resume study treatment and must continue to undergo assessments as per Table 1, 
including scans at 6-week intervals (or sooner if felt to be medically indicated) until PD is 
confirmed by BICR.  Those who begin subsequent non-study anti-cancer therapy prior to 
BICR-confirmed PD should continue to undergo tumour assessments, and sites must send 
each scan to the sponsor-designated vendor until PD is confirmed by BICR  
After the primary PFS analysis, central review of scans will no longer be required and 
investigators will be advised when to stop sending copies of the scans to the CRO conducting 
the central review.  The primary analysis of PFS for this study will be based on confirmation 
of PD using RECIST 1.1 by BICR. 
5.2 
Safety assessments 
5.2.1 
Laboratory safety assessments 
Blood and urine samples for determination of clinical chemistry, haematology, and urinalysis 
will be taken at the times indicated in the Study Plan (see Table 1).  
The following safety laboratory variables will be measured: 

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Table 2 
Standard Laboratory Safety Assessment Panel  
Clinical chemistry safety 
Haematology 
S/P-Albumin 
B-Absolute leucocyte differential count 
S/P-Alkaline phosphatase2 
B-Eosinophils 
S/P-ALT2 
B-Haemoglobin 
S/P-Amylase 
B-Leucocyte cell count 
S/P-AST2 
B-Lymphocytes 
S/P-Bilirubin, total2,4 
B-Neutrophils 
S/P-Calcium, total 
B-Platelet count 
S/P-Creatinine 
Urinalysis 
S/P-Free T43 
U-Dipstick-Blood 
S/P-Glucose 
U-Dipstick-Glucose 
S/P-HbsAg5, anti-HBc (qualitative), HBV 
DNA6, HCV antibody, HCV RNA7 
U-Dipstick-Ketones 
S/P-Lactate dehydrogenase3 
U-Dipstick- Leukocyte esterase or 
Leukocyte count 
S/P-Magnesium 
U-Dipstick-Protein1 
S/P-Phosphate 
 
S/P-Potassium 
 
S/P-Sodium 
 
S/P-Thyroid Stimulating Hormone3 
 
S/P-Total Protein 
 
S/P-Urea nitrogen 
 
1 
If 3+ or greater proteinuria is identified by dipstick assessment, a 24-hour urine collection for formal 
quantification of the level of protein excretion should be performed 
2 
Designates tests that are considered liver function tests (LFTs) and are to be done weekly x 9 and then at the 
start of every course thereafter.  Guidelines for management of hepatotoxicity are in section 6.8.1.2 for 
savolitinib and section 6.8.2 for sunitinib 
3 
Thyroid function studies and LDH are to be done at the main study (Part 2) screening visit, and at the start 
of every cycle thereafter 
4 
If total bilirubin is >2x ULN, then fractionate into indirect and direct bilirubin 
5 
If the HBsAg test is negative, the anti-HBc test should be still performed 
6 
HBV DNA test should be available for all patients that have had a previous HBV infection or are positive 
for HBsAg 
7 
HCV RNA qualitative test is only needed if the HCV Ab test is positive, and must be negative for the 
patient to be eligible. 

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Unscheduled blood or urine samples may need to be taken at the onset and as a part of a 
follow-up of some SAEs.  The results should be added to the clinical trial database. 
In case a patient shows an AST or ALT ≥3 x ULN and total bilirubin ≥2 x ULN please refer to 
Appendix E ‘Actions Required in Cases of Increases in Liver Biochemistry and Evaluation of 
Hy’s Law’, for further instructions.  
For blood volumes see Section 5.7.12 
5.2.2 
Physical examination 
For timing of individual measurement refer to study schedule (see Table 1).  
A complete physical examination will be performed and include an assessment of the 
following: general appearance, respiratory, cardiovascular, abdomen, skin, head and neck 
(including ears, eyes, nose and throat), lymph nodes, thyroid, musculoskeletal (including spine 
and extremities) and neurological systems. 
5.2.3 
ECG, ECHO/MUGA 
5.2.3.1 
Resting 12-lead ECG 
QTcF evaluation for the main study screening (Part 2) will be done based on triplicate 12 lead 
ECGs during the Part 2 screening period, every week in the first cycle, every cycle thereafter, 
and at the end of treatment as indicated in Table 1. Twelve-lead ECGs (triplicate) will be 
obtained after the patient has been rested in a supine position for at least 5 minutes. The 
investigator or designated physician will review the paper copies of the 12-lead ECGs. ECGs 
will be recorded at 25 mm/sec. All ECGs should be assessed by the investigator as to whether 
they are clinically significantly abnormal / not clinically significantly abnormal. If there is a 
clinically significant abnormal finding, the investigator will record it as an AE on the eCRF. 
The original ECG traces must be stored in the patient medical record as source data. A 28-day 
follow-up assessment will be required if an on-treatment assessment was abnormal at the time 
of discontinuation of study therapy, to confirm reversibility of the abnormality. 
5.2.3.2 
ECHO or MUGA 
An ECHO or MUGA scan to assess LVEF will be conducted during the main study (Part 2) 
screening period, every 12 weeks (±2 weeks) relative to the first dose of study medication, and 
at the end of treatment as indicated in Table 1.  The modality of the cardiac function 
assessments must be consistent within a patient ie, if echocardiogram is used for the screening 
assessment then echocardiograms should also be done for subsequent testing.  The patients 
should also be examined using the same machine and operator whenever possible. 

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5.2.4 
Vital signs 
Vital signs (heart rate, BP, temp) will be performed during the main study (Part 2) screening 
visit, during study treatment as per Table 1 and as clinically indicated. 
Height will be assessed at the main study (Part 2) screening visit only.  Weight will be 
assessed at the Part 2 screening visit, at the beginning of every cycle, and more frequently if 
clinically indicated.  The dose of savolitinib will not change for patients who started the 
study at <50 kg (ie, 400 mg), even if their weight increases to ≥50 kg during the course of 
the study.   
Any changes in vital signs should be recorded as an AE, if applicable. 
5.2.4.1 
Pulse and blood pressure 
Blood pressure and heart rate will be measured preferably using a semi-automatic BP 
recording device with an appropriate cuff size after 10 minutes rest on a bed.  Blood pressure 
and pulse will be measured as per Table 1 and as clinically indicated thereafter. 
The date of collection and measurement will be recorded on the appropriate eCRF. 
5.2.4.2 
Body temperature 
Body temperature will be measured in degrees Celsius using an automated thermometer at the 
times indicated in Table 1. 
The date of collection and measurement will be recorded on the appropriate eCRF. 
5.2.5 
Other safety assessments 
5.2.5.1 
Serum or urine pregnancy test 
A pregnancy test on urine or blood sample will be performed for pre-menopausal women of 
childbearing potential, at the study screening visit, and prior to the first dose of study drug on 
Cycle 1 Day 1, at regular intervals during the study (monthly or at the time of a scheduled 
visit) and at treatment discontinuation.  Tests will be performed by the institutional laboratory.  
If results are positive the patient is ineligible/must be discontinued from the study.  In the 
event of a suspected pregnancy during the study, the test should be repeated and if positive, 
the patient will be discontinued from study treatment immediately. 
5.3 
Other assessments 
5.3.1 
Patient Reported Outcomes 
Patient Reported Outcomes (PRO), an umbrella term referring to all outcomes and symptoms, 
as directly reported by the patient.  Patient Reported Outcomes have become a significant 
endpoint when evaluating effectiveness of treatments in clinical trials.  The sponsor obtained 
useful information about the effects of savolitinib in the phase II trial in PRCC, documenting 

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that patients appear to be stable in terms of their symptoms and their quality of life (as 
secondary endpoints) while on treatment.  The same PRO tools (with the addition of a fatigue 
module to form the FACIT-F rather than just the FACT-G will be used in this phase III trial to 
evaluate the treatment effects on symptoms and HRQoL in relation to a clinical comparator 
(sunitinib).  PRO questionnaires will be administered using PDAs (personal data assistant or a 
handheld PC).  
All patients should complete the questionnaire Functional Assessment of Cancer Therapy 
Kidney Symptom Index-19 (FKSI-19), Functional Assessment of Cancer Therapy – Fatigue 
(FACIT-F) and European Quality of Life-5 Dimensions-5 Levels (EQ-5D-5L) at the 
scheduled clinic visit at Cycle 1 Day 1 pre-dose, and throughout the study at the times 
specified in the study plan (Table 1).  The patient should continue to fill out the ePRO 
questionnaires until the EOT visit, at which time the last set will be completed by the patient.  
Health economic data will be collected until 30 days post-discontinuation of study medication 
(ie, the time of the Safety Visit).  The e-PRO device should be returned at the EOT visit 
following the decision to discontinue study medication. 
The site will train the patient on ePRO use during the first visit and have the patient fill 
out all four baseline questionnaires prior to any other activities, including being seen by 
the Investigator.  It should take approximately 20 minutes to complete the questionnaires 
after the training.  Thereafter, patients will be instructed to complete the PROs independently 
at home.  It is important that the value and relevance of PRO data are explained carefully to 
participating patients so that they are motivated to comply with data collection.  The research 
nurse or appointed individual should also stress that the information is confidential.  If the 
patient has any medical problems he/she should discuss them with the doctor or research nurse 
separately from their PRO assessment.  The site should check to ensure that the PRO data has 
been entered (ie, patient compliance) on the web-based portal during every site visit.  
Similarly, at the EOT visit, the patient should fill out all four questionnaires prior to 
being seen by the Investigator. 
The instructions for completion of questionnaires are as follows: 
 
The patient must complete the questionnaires themselves without any intervention from 
family, friends, centre staff etc. 
 
The only exception to this is if the patient is blind or illiterate.  In this case the 
questionnaires may be read to the patient verbatim, however the reader must not aid in the 
interpretation of questions or in the selection of answers. 
 
Only one answer to every question should be checked. 

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 
Should the patient come to the centre for a visit without having completed the 
assessments independently at home, they should do so while at the site visit.  In such 
cases: 
 
The assessments must be completed before any investigations or discussions about 
the patient’s disease with the clinic staff.    
 
 Centre personnel should not review the responses to the questions with the patient or 
with any other centre staff. 
 
5.3.1.1 
Functional Assessment of Chronic Illness Therapy – Fatigue  
The validated Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) (now in 
Version 4) is a 40-item instrument.  It comprises the 4 domains from the FACT-G (Physical 
Well-Being, Social/Family Well-Being, Emotional Well-Being, and Functional Well-Being) 
as well as a 13-item 'additional concerns' domain that captures information about fatigue. 
(Appendix I). 
5.3.1.2 
Functional Assessment of Cancer Therapy Kidney Symptom Index-19  
The Functional Assessment of Cancer Therapy Kidney Symptom Index-19 (FKSI-19) is a 
validated instrument designed to accurately assess patient self-reported symptom burden to 
determine treatment impact and evaluate clinical benefit in patients with renal cancer (Rao et 
al 2009).  The instrument includes 19 items covering 4 subscales: Disease-Related Symptoms 
Subscale – Physical, Disease-Related Symptoms Subscale – Emotional, Treatment Side 
Effects Subscale, Function and Well-Being Subscale; responses are reported as it applies to 
the past 7 days (Appendix J). 
5.3.1.3 
European Quality of Life-5 Dimensions-5 Levels 
The EQ-5D is a standardised measure of health status developed by the European Quality of 
Life (EuroQoL) Group in order to provide a simple, generic measure of health for economic 
appraisal (EuroQoL Group 2015), see Appendix J.  Applicable to a wide range of health 
conditions and treatments, it provides a simple descriptive profile and a single index value for 
health status that can be used in the economic evaluation of health care.  The questionnaire 
assesses 5 dimensions: mobility, self-care, usual activities, pain/discomfort, and 
anxiety/depression.  Each dimension has 5 response options (no problems, slight problems, 
moderate problems, severe problems, and extreme problems) that reflect increasing levels of 
difficulty (EuroQoL Group 2015).  The patient will be asked to indicate his/her current health 
state by selecting the most appropriate level in each of the 5 dimensions.  The questionnaire 
also includes a visual analogue scale (VAS), where the patient will be asked to rate their 
current health status on a scale of 0 to 100, with zero being the worst imaginable health state. 
5.3.1.4 
PRO CTCAE 
The Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse 
Events (PRO-CTCAE) system has been developed by the National Cancer Institute (NCI).  

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The PRO-CTCAE will only be administered in the US, Italy, France, and South Korea where 
a linguistically-validated version exists.  PRO-CTCAE is an item-bank of symptoms 
experienced by patients while undergoing treatment of their cancer.  It was developed in 
recognition that collecting symptom data directly from patients using PRO tools can improve 
the accuracy and efficiency of symptomatic AE data collection.  This was based on findings 
from multiple studies demonstrating that physicians and nurses underestimate symptom onset, 
frequency, and severity in comparison with patient ratings (Sprangers et al 1992; Litwin et al 
1999; Basch et al 2009).  To date, 81 symptoms of the CTCAE have been identified to be 
amenable to patient reporting.  These symptoms have been converted to patient terms (eg, 
CTCAE term “myalgia” converted to “aching muscles”).  For several symptoms, like fatigue 
and pain, additional questions are asked about symptom frequency, severity, and interference 
with usual activities.  For other symptoms like rash, additional questions focus on the presence 
on the body.  The items included in the PRO-CTCAE have undergone extensive qualitative 
review among experts and patients.  These items and the additional questions for some of the 
symptoms have been extensively evaluated by cancer patients, using cognitive testing 
methods, to be clear, comprehendible, and measure the symptom of interest.  Not all items are 
administered in any one clinical trial.  The questionnaire in Appendix J contains only those 
items which are considered relevant for the trial, site of cancer, and cancer treatment. 
5.3.2 
Hospital resource use 
Site staff should review hospital notes for any hospital visits and procedures that were not part 
of the study visits and complete the AZ Hospital Admissions (HOSPAD) oncology module as 
required starting Cycle 1 Day1 of the study and for 30 days post-drug discontinuation until the 
Safety Follow-up visit. 
HOSPAD is a short form that the site staff should complete whenever the patient attends any 
inpatient or outpatient hospital visit that is not part of the study protocol, including 
admissions, ER visits etc.  The form asks for information on the type of visit (ER, clinic, 
hospital stay, and ICU) and length of stay where relevant.  In addition, it contains a list of 
presenting symptoms /signs that the patient has upon arrival.  If the patient requires a 
hospitalisation, HOSPAD automatically reminds the study staff to complete the SAE 
modules.   
5.4 
 Pharmacokinetics 
5.4.1 
Collection of samples 
Venous blood samples (2 mL) will be collected from patients receiving savolitinib at the times 
detailed in Table 1 and Table 3 for determination of plasma concentrations of savolitinib, and 
of M2 and M3, the major metabolites of savolitinib.  The date/time of the last two doses given 
prior to the PK sample, as confirmed in the patient diary, as well as the date/time the PK 
sample is drawn and the dose/time that savolitinib is given on the PK day need to be recorded 

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in the eCRF.  Plasma concentrations will be analysed by Covance on behalf of AstraZeneca, 
using an appropriate bioanalytical method.  Full details of the analytical method used will be 
described in a separate bioanalytical report.  
In addition, a 2-mL blood sample for PK analysis should be drawn as soon as feasible after the 
patient is diagnosed with abnormal LFTs necessitating drug interruption.  The date and time of 
the last savolitinib dose must be recorded in the eCRF. 
Table 3 
Pharmacokinetic savolitinib blood sampling schedule 
Day 
Time for blood sample collection (2 mL) 
Cycle 1 Day 1 
Single Sample: Pre-dose 
Cycle 1 Day 15 
Pre-Dose, and 1 and 3 hours post-dosing 
Cycle 1, Day 29 
Single Sample: Pre-dose 
Cycle 2, Day 15 (day 57) 
Single Sample: Pre-dose 
At the time that the patient is diagnosed with 
abnormal LFTs necessitating drug 
interruption. 
ASAP after abnormal LFTs necessitating 
drug interruption. 
Samples will be collected, labelled, stored and shipped as detailed in the Laboratory Manual.  
 
5.4.2 
Determination of drug concentration 
Samples for determination of drug concentration in plasma will be analysed by the 
sponsor-designated laboratory, using an appropriate bioanalytical method.  Full details of the 
analytical method used will be described in a separate bioanalytical report. 
5.4.3 
Storage and destruction of pharmacokinetic samples 
Pharmacokinetic (PK) samples will be disposed of after the Bioanalytical Report finalisation 
or 6 months after issuance of the draft Bioanalytical Report (whichever is earlier), unless 
requested for future analyses.   
Pharmacokinetic samples may be disposed of or destroyed and anonymised by pooling. 
Additional analyses may be conducted on the anonymised, pooled pharmacokinetic samples to 
further evaluate and validate the analytical method.  Any results from such analyses may be 
reported separately from the CSR.  
Incurred sample reproducibility analysis, if any, will be performed alongside the bioanalysis 
of the test samples.   The results from the reproducibility evaluation will not be reported in the 
Clinical Study Report, but separately in a Bioanalytical Report. 

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Any residual back-up PK samples may be used for future 
 (in 
this case, residual back-up PK samples will be shipped to AstraZeneca Biobank, see details in 
the Laboratory Manual). 
5.5 
Pharmacodynamics 
5.5.1 
Collection of samples 
Pharmacodynamic samples from blood will not be collected during the study.  However, on 
treatment tumour samples from patients who have had a response or stabilisation on either 
drug can be collected at the time of relapse 
  
5.6 
Pharmacogenetics (Appendix C) 
The subject’s consent to participate in the genetic research components of the study is 
optional.  The background, rationale, objectives, and inclusion/exclusion criteria for the 
genetic analysis are detailed in Appendix C: Genetics Research.  Please refer to Appendix C 
and the Laboratory manual for further information surrounding the timing of blood sample 
collection, storage, and destruction.   
5.7 
Biomarker analysis  
Biological samples (eg, tumour or blood) will be collected as detailed in the Laboratory 
Manual for the reasons listed below: 
 
  
 
 
 
 
5.7.1 
NGS analysis to determine MET-driven status of tumour biopsy sample 
See section 5.7.2 for information on appropriate specimens for Part 1 screening. The 
Laboratory Manual provides the required tissue specifications.   
The tumour sample will be used to test for the following molecular alterations: 
 
Chromosome 7 gain  
 
MET amplification 
 
MET kinase domain mutations  
 
HGF amplification 
 
 FH mutation 
 
VHL mutation 
 
Genomic alterations in chromosome 7, MET or HGF genes will be used to determine MET- 
status and potential eligibility for the main study. 

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Genomic alterations in FH and VHL genes will be used to exclude patients, as described in 
Section 1.2.5. 
5.7.2 
Collection, analysis and reporting of tumour samples 
Following the Part 1 screening visit and signing of the ICF, an FFPE tumour sample meeting 
the requirements specified in the Laboratory Manual will be sent to the sponsor-designated 
central laboratory.  For first-line patients, the diagnostic specimen should be used.  For 
previously treated patients, the most recent archival specimen obtained during a clinical 
procedure is preferable to the diagnostic specimen only if it meets specifications and has an 
equal or higher tumour cellularity.  Fine needle aspirate FFPE cell blocks will not provide 
sufficient tumour and as such are not allowed.  
If the above is not available or unlikely to yield sufficient material for testing, the patient will 
have the option to provide an FFPE tumour tissue block from a de-novo core needle tumour 
biopsy.  The biopsied tumour should preferably not be a RECIST target lesion. Consideration 
should be given to the potential benefit to the patient (should they be eligible for the main 
study) in the context of the risk posed by the biopsy procedure.  Tissue biopsy sampling 
should be conducted in appropriate clinical settings in accordance with expert guidelines, only 
by investigators experienced in performing these sampling methods.  
Please refer to the Laboratory Manual for further details regarding sample selection, retesting 
procedures etc. 
For each sample that passes tissue sample quality control, the sponsor-designated central 
laboratory will generate a clinical trial assay (CTA) report detailing the presence or absence of 
qualifying genomic alterations for MET-driven status.  
5.7.3 
Exploratory use of data generated from the sponsor-designated central 
laboratory testing of tumour samples  
The designated, investigational SAVOIR clinical trial NGS assay involves the analysis of 
2 genes and chromosome 7 data for the presence of qualifying alterations (ie, MET-driven) 
and of 2 genes for the presence of alterations governing exclusion in this study.  The 
underlying gene panel used in this investigational test is based on the sponsor designated 
central laboratory’s clinical-grade cancer gene profiling test which analyses the coding 
sequence of 310 cancer-related genes plus select introns from 31 genes for variants and/or 
rearrangements.  A full list of all genes is available in the Laboratory Manual. 
 
 
  

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The results of the biomarker analysis of the other cancer-related genes can be requested by the 
investigator under the conditions outlined in the Genomic Testing Manual.  
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 

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5.7.7 
Collection of tumour samples for exploratory analysis at disease 
progression (optional) 
All patients will be asked to provide consent (in the Main ICF or at EOT) for a biopsy for 
fresh tumour tissue at disease progression (see Laboratory Manual for specifics).  This biopsy 
is strongly encouraged, but optional.  Such collections are particularly encouraged for patients 
who derived benefit from study medication and subsequently relapse or discontinue 
drug.  This sample will be used to help understand the mechanisms of relapse to either study 
medication.  
5.7.8 
Storage, re-use and destruction of biological samples 
Samples will be stored for a maximum of 15 years from the date of the Last Subject Last 
Visit, after which they will be destroyed.  The results of this biomarker research will be 
reported either in the Clinical Study Report itself or as an addendum, or separately in a 
scientific report or publication.  The results of this biomarker research may be pooled with 
biomarker data from other studies with the study medication to generate hypotheses to be 
tested in future research. 
5.7.9 
Labelling and shipment of biological samples (Appendix B) 
The Principal Investigator ensures that samples are labelled and shipped in accordance with 
the Laboratory Manual and the Biological Substance, Category B Regulations (materials 
containing or suspected to contain infectious substances that do not meet Category A criteria) 
see Appendix B‘IATA 6.2 Guidance Document’.  Any samples identified as Infectious 
Category A materials are not shipped and no further samples will be taken from the patient 
unless agreed with AstraZeneca and appropriate labelling, shipment and containment 
provisions are approved. 
5.7.10 
Chain of custody of biological samples  
A full chain of custody is maintained for all samples throughout their lifecycle. 
The Principal Investigator at each centre keeps full traceability of collected biological samples 
from all patients while in storage at the centre until shipment or disposal (where appropriate) 
and keeps documentation of receipt of arrival. 
The sample receiver keeps full traceability of the samples while in storage and during use until 
used or disposed of or until further shipment and keeps documentation of receipt of arrival. 
AstraZeneca keeps oversight of the entire life cycle through internal procedures, monitoring of 
study sites and auditing of external laboratory providers. 
Samples retained for further use are registered in the AstraZeneca Biobank during the entire 
life cycle. 

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5.7.11 
Withdrawal of Informed Consent for donated biological samples  
If a patient withdraws consent to the use of donated biological samples, the samples will be 
disposed of/destroyed, and the action documented.  If samples are already analysed, 
AstraZeneca is not obliged to destroy the results of this research. 
The Principal Investigator: 
 
Ensures that AstraZeneca is notified immediately of the patients’ withdrawal of informed 
consent for the use of donated samples.  
 
Ensures that biological samples from that patient, if stored at the study site, are 
immediately identified, disposed of /destroyed, and the action documented. 
 
Ensures the organisation(s) holding the samples is/are informed about the withdrawn 
consent immediately and that samples are disposed of/destroyed, the action documented 
and the signed document returned to the study site. 
 
Ensures that the patient and AstraZeneca are informed about the sample disposal. 
 
AstraZeneca ensures the organisation(s) holding the samples is/are informed about the 
withdrawn consent immediately and that samples are disposed of/destroyed and the action 
documented and returned to the study site. 
5.7.12 
Volume of blood 
The volume of blood that will be drawn from each patient during the study will vary 
depending upon the length of participation, patient consent to 
 
 and standard practices. 
Safety laboratory assessments will be performed locally at each centre’s laboratory by means 
of established methods.  The number of samples/volumes is therefore subject to 
centre-specific changes.  Extra blood samples may also be collected if, for example, additional 
samples are required for repeat safety assessments or additional PK assessment. 
The total volume of blood drawn from each patient receiving a minimum of 24 weeks of 
treatment in this study is as follows: 

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Table 7 
Volume of blood to be drawn from each patient in the first 24 weeks 
Assessment 
Sample volume 
(mL) 
No. of 
samples 
Total volume 
(mL) 
Safety 
Clinical chemistries and 
LFTs (including thyroid 
hormones, LDH) 
8 mL 
5 
40 
 
Clinical chemistry and 
LFTs 
4 mL 
4 
16 
 
LFTs 
4 mL 
4 
16 
 
Hepatic screening 
8 mL 
1 
8 
 
Haematology 
4 mL 
9 
36 
 
Coagulation 
5 mL 
1 
5 
Pharmacokinetics  
2 mL 
6 
12 
 
10 mL 
3 
30 
 
 
10 mL 
6 
60 
 
20 mL 
1 
20 
Pharmacogenetics (optional) 
10 mL 
1 
10 
Total 
 
41 
253 
6. 
SAFETY REPORTING AND MEDICAL MANAGEMENT 
Liver enzyme and bilirubin abnormalities, as well as any clinical adverse events associated 
with liver dysfunction will be reported on a quarterly basis to the FDA.   
The Principal Investigator is responsible for ensuring that all staff involved in the study are 
familiar with the content of this section. 
6.1 
Definition of adverse events 
An adverse event is the development of any untoward medical occurrence in a subject or 
clinical study subject administered a medicinal product and which does not necessarily have a 
causal relationship with this treatment.  An AE can therefore be any unfavourable and 
unintended sign (eg, an abnormal laboratory finding), symptom (for example nausea, chest 
pain), or disease temporally associated with the use of a medicinal product, whether or not 
considered related to the medicinal product.  

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The term AE is used to include both serious and non-serious AEs and can include a 
deterioration of a pre-existing medical occurrence.  An AE may occur at any time, including 
run-in or washout periods, even if no study treatment has been administered. 
6.1.1 
AEs of special interest – hepatic disorders 
A thorough review of the patients who developed significant hepatotoxicity on savolitinib was 
undertaken.  As of 30 August 2016, 387 patients/healthy volunteers have received at least 
1 dose of savolitinib.  Of these, 108/325 (33%) reported 303 AEs in the Hepatic Disorders 
SMQ. Per-patient multiple hepatic event reporting, either simultaneously or sequentially, was 
frequent.  The most common hepatic AE was an increase in liver enzyme values (ALT, AST, 
ALP, or bilirubin) accounting for 221/303 events (73%), of which 22/303 (7.2%) events were 
serious.  Overall, most liver enzyme AEs were considered by the investigator to be related to 
study medication (171/221 events, 77%).  Most were mild or moderate in severity (171/221 
events, 77%), and resolved without reduction or interruption of savolitinib (164/221 events, 
74%).  Fifteen of 22 serious hepatic events were considered causally related to savolitinib and 
4/22 not related. 
The onset of hepatic toxicity was within 1 week of exposure for 52/221, 23% of events.  Over 
the subsequent 3 weeks, a further 110/221, 50%, events began; however, later events can 
develop.  Ninety-five percent of events occur within the first 10 weeks.  Time to resolution 
was up to one week in 30/303, 10%; 85/303, 28%, took between 1 and 2 weeks to resolve and 
55/303, 18%, took 2 to 4 weeks to resolve.  Ten patients had combined bilirubin and 
ALT/AST elevations consistent with potential Hy’s law.  Three of these patients had no other 
explanation for the liver biochemistry abnormalities other than liver injury caused by the 
savolitinib and therefore met the criteria for Hy’s law.  One of these 3 patients experienced a 
fatal event of hepatic encephalopathy and the investigator felt that there was a reasonable 
possibility that the event may have been caused by the savolitinib.   
The hepatic adverse effect profile of savolitinib is similar to other tyrosine kinase inhibitors 
(TKIs), ie, a high frequency of low grade enzyme elevations and much less frequent 
higher-grade enzyme elevations.  In general, with savolitinib, these events resolve within 
2 months without dose changes.  Possible confounders, the majority of which were 
concomitant medications with labelled hepatic adverse reactions, were of numerically limited 
influence, ie, reported in no more than 25% of adverse events.  The hepatic event profile of 
savolitinib is likely to be a true drug effect, given its frequency and its consistency with other 
TKIs.  The severity is generally low, the events are self-limiting, while being slow to resolve. 
Dose changes or drug discontinuation occurred in 25% of the events.  On savolitinib, a rise in 
hepatic enzymes or bilirubin requires close monitoring until resolution, and if persistent or 
increasing in severity, the study medication should be interrupted or discontinued. Some 
patients can be successfully re-challenged at a lower dose and those with lower-grade 
elevations may be able to continue the drug with subsequent improvement.  

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Pharmacokinetic/pharmacodynamic modelling of hepatotoxicity data as of 30 June 2016 
showed a link between exposure (AUC and Cmin) and high-grade liver elevations. Preliminary 
univariate extreme value modelling showed a weak-to-moderate level of evidence of a 
relationship between BW (body weight) and maximum LFT elevation.  Patients with lower 
body weights may therefore be at greater risk of hepatotoxicity.  A BW cut-off of 50 kg is 
predicted to 1) provide maximum exposures in line with the upper 90% percentile of heavier 
individuals, perhaps reducing hepatotoxicity risk and 2) provide minimum exposures above 
the minimum predicted exposure associated with the 600 mg QD dosing.  Higher cut-offs may 
result in exposures significantly below the observed 600 mg QD exposure range.  Therefore, a 
400-mg dose for patients below 50 kg will be used to potentially reduce the risk of 
hepatotoxicity. 
6.2 
Definitions of serious adverse event 
A serious adverse event is an AE occurring during any study phase (ie, run-in, treatment, 
washout, follow-up), that fulfils one or more of the following criteria: 
 
Results in death. 
 
Is immediately life-threatening. 
 
Requires in-patient hospitalisation or prolongation of existing hospitalisation.  
 
Results in persistent or significant disability or incapacity. 
 
Is a congenital abnormality or birth defect. 
 
Is an important medical event that may jeopardise the patient or may require medical 
intervention to prevent one of the outcomes listed above. 
 
For further guidance on the definition of a SAE, see Appendix A to the Clinical Study 
Protocol. 
6.3 
Recording of adverse events 
6.3.1 
Time period for collection of adverse events 
In the Part 1 screening period, only SAEs related to study procedures must be reported (AEs 
do not require reporting).  From the signature of the main (Part 2) ICF onwards, throughout 
the treatment period and up to and including the 30-day follow-up period all AEs/SAEs must 
be reported. 
6.3.2 
Follow-up of unresolved adverse events 
Any AE/ SAE/ abnormal laboratory findings that are ongoing at the time of study treatment 
discontinuation or any new treatment related events within 30 days of last study treatment, 
must be followed up to resolution or until the event becomes stable (or returns to baseline) or 
is unlikely to resolve further in the opinion of the investigator.  AstraZeneca retains the right 

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to request additional information for any patient with ongoing AE(s)/SAE(s) at the end of the 
study, if judged necessary.  
6.3.3 
Variables  
The following variables will be collect for each AE; 
 
AE (verbatim). 
 
The date and time when the AE started and stopped. 
 
Worst CTCAE grade and changes in grade during the course of the AE.  
 
Whether the AE is serious or not. 
 
Investigator causality rating against the Investigational Product (IP) (yes or no). 
 
Action taken with regard to IP. 
 
AE resulted in patient’s withdrawal from study (yes or no). 
 
Outcome. 
 
In addition, the following variables will be collected for SAEs: 
 
Date AE met criteria for serious AE. 
 
Date Investigator became aware of serious AE. 
 
AE is serious due to (provide all seriousness criteria applicable). 
 
Date of hospitalisation (if applicable). 
 
Date of discharge (if applicable). 
 
Probable cause of death (if applicable). 
 
Date of death (if applicable). 
 
Autopsy performed (if applicable). 
 
Causality assessment in relation to Study procedure(s). 
 
Causality assessment to other medication. 
 
Description of AE. 
 
It is important to distinguish between serious and severe AEs.  Severity is a measure of 
intensity whereas seriousness is defined by the criteria in Section 6.2.  An AE of severe 
intensity need not necessarily be considered serious.  For example, nausea that persists for 
several hours may be considered severe nausea, but not a SAE unless it meets the criteria 
shown in Section 6.2.  On the other hand, a stroke that results in only a limited degree of 
disability may be considered a mild stroke but would be a SAE when it satisfies the criteria 
shown in Section 6.2. 
The grading scales found in the National Cancer Institute (NCI) CTCAE will be utilised for all 
events with an assigned CTCAE grading.  For those events without assigned CTCAE grades 

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the recommendation is that the CTCAE criteria that convert mild, moderate and severe events 
into CTCAE grades should be used. 
A copy of the CTCAE version can be downloaded from the Cancer Therapy Evaluation 
program website (http://ctep.cancer.gov). 
6.3.4 
Causality collection 
The investigator will assess causal relationship between Investigational Product and each 
Adverse Event, and answer ‘yes’ or ‘no’ to the question ‘Do you consider that there is a 
reasonable possibility that the event may have been caused by the investigational product?’ 
For SAEs causal relationship will also be assessed for other medication and study procedures.  
Note that for SAEs that could be associated with any study procedure the causal relationship is 
implied as ‘yes’. 
A guide to the interpretation of the causality question is found in Appendix A to the Clinical 
Study Protocol. 
6.3.5 
Adverse events based on signs and symptoms 
All AEs spontaneously reported by the patient during the visit or in the eDiary or reported in 
response to the open question from the study site staff: ‘Have you had any health problems 
since the previous visit/you were last asked?’, or revealed by observation will be collected and 
recorded in the eCRF. When collecting AEs, the recording of diagnoses is preferred (when 
possible) to recording a list of signs and symptoms.  However, if a diagnosis is known and 
there are other signs or symptoms that are not generally part of the diagnosis, the diagnosis 
and each sign or symptom will be recorded separately. 
6.3.6 
Adverse events based on examinations and tests 
The results from the Clinical Study Protocol mandated laboratory tests and vital signs will be 
summarised in the CSR.  Deterioration as compared to baseline in protocol-mandated 
laboratory values or vital signs or cardiac evaluations should therefore only be reported as 
AEs if they fulfil any of the SAE criteria or are the reason for discontinuation of treatment 
with the investigational product. 
If deterioration in a laboratory value/vital sign is associated with clinical signs and symptoms, 
the sign or symptom will be reported as an AE and the associated laboratory result/vital sign 
will be considered as additional information.  Wherever possible the reporting investigator 
uses the clinical, rather than the laboratory term (eg, anaemia versus low haemoglobin value).  
In the absence of clinical signs or symptoms, clinically relevant deteriorations in non-
mandated parameters should be reported as AE(s). 

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Deterioration of a laboratory value, which is unequivocally due to disease progression, should 
not be reported as an AE/SAE. 
Any new or aggravated clinically relevant abnormal medical finding at a physical examination 
as compared with the baseline assessment will be reported as an AE. 
6.3.7 
Hy’s Law 
Cases where a patient shows elevations in liver biochemistry may require further evaluation 
and occurrences of AST or ALT ≥3xULN together with total bilirubin ≥2xULN may need to 
be reported as SAEs.  Please refer to Section 6.8.1.2 and Appendix E for further instruction on 
cases of increases in liver biochemistry and evaluation of Hy’s Law.   
6.3.8 
Disease progression 
Disease progression can be considered as a worsening of a patient’s condition attributable to 
the disease for which the investigational product is being studied.  It may be an increase in the 
severity of the disease under study (DUS) and/or increases in the symptoms of the cancer.  
The development of new, or progression of existing metastasis to the primary cancer under 
study should be considered as disease progression and not an AE.  Events, which are 
unequivocally due to disease progression, should not be reported as an AE during the study.  
6.4 
Reporting of serious adverse events 
All SAEs have to be reported, whether or not considered causally related to the investigational 
product, or to the study procedure(s).  All SAEs will be recorded in the eCRF. 
If any SAE occurs in the course of the study, then investigators or other site personnel inform 
the appropriate AstraZeneca representatives within 1 day ie, immediately but no later than 
24 hours of when he or she becomes aware of it. 
The designated AstraZeneca representative works with the investigator to ensure that all the 
necessary information is provided to the AstraZeneca Patient Safety data entry site within 
1 calendar day of initial receipt for fatal and life-threatening events and within 5 calendar 
days of initial receipt for all other SAEs. 
For fatal or life-threatening adverse events where important or relevant information is missing, 
active follow-up is undertaken immediately.  Investigators or other site staff inform 
AstraZeneca representatives of any follow-up information on a previously reported SAE 
within one calendar day ie, immediately but no later than 24 hours of when he or she 
becomes aware of it. 

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Once the investigators or other site personnel indicate an AE is serious in the Web Based Data 
Capture (WBDC system), an automated email alert is sent to the designated AstraZeneca 
representative. 
If the WBDC system is not available, then the investigator or other study site personnel 
reports a SAE to the appropriate AstraZeneca representative by telephone. 
The AstraZeneca representative will advise the investigator/study site staff how to proceed.  
The reference safety document for the definition of expectedness/listedness is Section 5.4 of 
the Investigator’s Brochure for savolitinib and the EU Summary of Product Characteristics 
(SPC) for the active comparator, sunitinib.  
6.5 
Overdose 
Overdose is defined as the accidental or intentional ingestion of any dose of investigational 
product that is considered both excessive and medically important. For further dosing 
information please refer to the IB.  
 
An overdose with associated AEs is recorded as the AE diagnosis/symptoms on the 
relevant AE modules in the eCRF and on the Overdose eCRF module. 
 
An overdose without associated symptoms is only reported on the Overdose eCRF 
module. 
 
If an overdose on an AstraZeneca study medication occurs in the course of the study, then the 
investigator or other site personnel inform appropriate AstraZeneca representatives 
immediately, or no later than 24 hours of when he or she becomes aware of it. 
The designated AstraZeneca representative works with the investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site. 
For overdoses associated with an SAE, the standard reporting timelines apply, see Section 6.4.  
For other overdoses, reporting must occur within 30 days. 
6.6 
Pregnancy 
All pregnancies occurring during the study in patients taking savolitinib, and their outcomes, 
should be reported to AstraZeneca except when the pregnancy is discovered before the study 
subject has received any study medication.  Pregnancies and their outcomes in female partners 
of patients occurring up to 6 months after the male patient has discontinued savolitinib should 
be reported to AstraZeneca.  Pregnancies occurring during the study in patients on sunitinib 
should be reported both to AstraZeneca and to Pfizer.   

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6.6.1 
Maternal exposure 
If a patient becomes pregnant during the course of the study, the study medication should be 
discontinued immediately. 
For patients taking savolitinib, pregnancy itself is not regarded as an adverse event unless 
there is a suspicion that the investigational product under study may have interfered with the 
effectiveness of a contraceptive medication.  Congenital abnormalities/birth defects and 
spontaneous miscarriages should be reported and handled as SAEs for patients taking 
savolitinib.  Elective abortions without complications should not be handled as AEs.  The 
outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, 
normal birth or congenital abnormality) should be followed up and documented even if the 
patient was discontinued from the study.  If pregnancy occurs in patients taking sunitinib 
during the course of the study, adverse outcomes as listed above, should be reported as SAEs 
to AstraZeneca and Pfizer. 
If any pregnancy occurs in patients during the course of the study, then the investigator or 
other site personnel informs the appropriate AstraZeneca representatives within 1day ie, 
immediately but no later than 24 hours of when he or she becomes aware of it.  The 
designated AstraZeneca representative works with the investigator to ensure that all relevant 
information is provided to the AstraZeneca Patient Safety data entry site within 1 or 
5 calendar days for SAEs (see Section 6.4) and within 30 days for all other pregnancies.  
The same timelines apply when outcome information is available. 
6.6.2 
Paternal exposure  
Because studies in animals taking savolitinib have shown abnormalities in sperm 
development, male patients taking savolitinib should refrain from fathering a child or donating 
sperm during the study and for 6 months following their last dose. 
Pregnancy in the partner of a patient is not considered to be an AE.  However, the outcome of 
all pregnancies in partners of patients taking savolitinib (spontaneous miscarriage, elective 
termination, ectopic pregnancy, normal birth or congenital abnormality) should if possible be 
followed up and documented in the Pregnancy Outcome Reporting Form.  Consent from the 
pregnant partner must be obtained (Pregnant Partner ICF) before the Pregnancy Outcome 
Reporting Form is completed.   
6.7 
Medication error 
For the purposes of this clinical study a medication error is an unintended failure or mistake in 
the treatment process for an AstraZeneca study medication that either causes harm to the 
subject or has the potential to cause harm to the subject.  

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A medication error is not lack of efficacy of the drug, but rather a human or process related 
failure while the drug is in control of the study site staff or subject. 
Medication error includes situations where an error:  
 
Occurred. 
 
was identified and intercepted before the subject received the drug. 
 
did not occur, but circumstances were recognised that could have led to an error. 
 
Examples of events to be reported as medication errors: 
 
Drug name confusion. 
 
Dispensing error eg, medication prepared incorrectly, even if it was not actually given to 
the patient. 
 
Drug not administered as indicated, for example, wrong route or wrong site of 
administration. 
 
Drug not taken as indicated eg, tablet dissolved in water when it should be taken as a 
solid tablet.  
 
Drug not stored as instructed eg, kept in the fridge when it should be at room temperature.  
 
Wrong patient received the medication (excluding IVRS/IWRS errors). 
 
Wrong drug administered to patient (excluding IVRS/IWRS errors). 
 
Examples of events that do not require reporting as medication errors in clinical studies: 
 
Errors related to or resulting from IVRS/IWRS - including those which lead to one of the 
above listed events that would otherwise have been a medication error.  
 
Subject accidentally missed drug dose(s) eg, forgot to take medication. 
 
Accidental overdose (will be captured as an overdose). 
 
Patient failed to return unused medication or empty packaging. 
 
Errors related to background and rescue medication, or standard of care medication in 
open label studies, even if an AZ product. 
 
Medication errors are not regarded as AEs but AEs may occur as a consequence of the 
medication error.   
If a medication error occurs in the course of the study, then the Investigator or other site 
personnel informs the appropriate AstraZeneca representatives within 1 day ie, immediately 
but no later than 24 hours of when he or she becomes aware of it. 

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The designated AstraZeneca representative works with the Investigator to ensure that all 
relevant information is completed within 1 or 5 calendar days if there is an SAE associated 
with the medication error (see Section 6.4) and within 30 days for all other medication errors. 
6.8 
Management of study medication-related toxicities - dose 
reductions and modifications 
Toxicity will be assessed utilizing the NCI CTCAE (https://evs.nci.nih.gov/ftp1/CTCAE/), 
unless otherwise specified.   
Table 8 outlines the Dose Level Reductions for each study medication.  A maximum of two 
dose reductions will be allowed for both drugs, unless the patient has started at a savolitinib 
dose of 400 mg due to weight <50 kg, where only one dose reduction is allowed. No dose 
re-escalations are allowed.  Immediate management of situations not covered by the 
guidelines below should be as medically indicated and with temporary suspension of study 
medication as appropriate, with follow up management carried out in consultation with the 
AstraZeneca study physician. 
Table 8 
Dose level reductions of study medications 
Dose level 
Savolitinib PO daily 
dose 
Sunitinib PO daily dose 
4 weeks on/2 weeks off 
Starting dose 
600 mg QD 
50 mg 
-1 Dose level 
400 mg QD 
37.5 mg 
-2 Dose level 
200 mg QD 
25 mg 
PO, Oral; QD, Once daily 
 
6.8.1 
Management of savolitinib-related toxicities 
Dose modification guidelines for savolitinib study drug-related toxicities are provided in the 
following sections.  Appropriate and optimal treatment of the toxicity is assumed prior to 
considering dose modifications.  Prior to discontinuation of study drug due to toxicities please 
consult with the AstraZeneca study physician.  Please see Section 6.8.1.1 for management of 
savolitinib-specific toxicities including dermatologic toxicity, pyrexia and hypersensitivity, 
Section 6.8.1.2 for hepatotoxicity management guidelines, Section 6.8.1.3 for dose 
modifications due to other savolitinib-related toxicity, Section 6.8.1.4 for dose modifications 
for savolitinib-related QTcF prolongation, and Section 6.8.1.5 for risk minimisation activities 
for identified and potential risks associated with savolitinib. 

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6.8.1.1 
Guidance for management of savolitinib specific toxicities 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
6.8.1.2 
Dose modification due to savolitinib-related hepatotoxicity  
 
Promptly evaluate patients with elevated LFTs during study treatment for alternative 
aetiologies and potential Hy’s law criteria (ALT or AST ≥3x ULN together with TBL 
≥2xULN) and discontinue potential contributing concomitant medications or alternative 
causal agents, as well as anti-coagulants, if appropriate. 

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 
Ensure a PK sample is collected as soon as feasible after the patient is diagnosed with 
abnormal LFTs necessitating drug interruption.  The date and time that the PK sample 
was drawn and the date and time of the last savolitinib dose prior to the PK sample must 
be recorded in the eCRF. 
 
If a patient discontinues due to an LFT abnormality, LFT monitoring should continue until 
resolution to grade 1 or baseline or an apparent plateau has been reached. 
1 
Discontinue savolitinib if 
 
ALT or AST >8x ULN, or 
 
ALT or AST >5x ULN for >2 weeks, or 
 
ALT or AST >3x ULN and (TBL>2x ULN or INR>1.5 if not on anticoagulants that 
elevate the INR). 
 
AST or ALT >3x ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia >5% 
2 
Withhold savolitinib if ALT or AST >5-8x ULN without TBL elevation above baseline or 
ULN, repeat LFT testing twice a week for 1 week;  
 
If improved to grade 1 or baseline in 1 week, resume at reduced dose with LFT 
testing twice a week for 6 weeks; 
 
If not, discontinue 
3 
Withhold savolitinib if ALT or AST >3x ULN and concurrent TBL 1.5~2x ULN, repeat 
LFT testing twice a week for 1 week,  
 
If both ALT/AST and TBL improve to grade 1 or baseline in 1 week, resume at 
reduced dose with LFT testing twice a week for 6 weeks 
 
If not, discontinue 
4 
Continue savolitinib if ALT or AST >3-5x ULN without TBL elevation above baseline or 
ULN, repeat LFT testing every week 
 
If ALT or AST are trending upward, withhold dosing and repeat LFT twice a week 
for 1 week; 
 
if improved to grade 1 or baseline in 1 week, resume at same dose with LFT testing 
every week for 6 weeks 
 
if improved to grade 1 or baseline in 2 weeks, resume at reduced dose with LFT 
testing every week for 6 weeks 
 
If not, discontinue 
5 
Discontinue savolitinib for recurrent Grade 3 ALT or AST (>5x ULN) 
6 
Discontinue savolitinib for recurrent Grade 2 ALT or AST (>3-5x ULN) and TBL 
>1.5~2x ULN 
7 
Withhold savolitinib for recurrent Grade 2 ALT or AST >3-5x ULN without TBL 
elevation above baseline or ULN, repeat LFT testing twice a week for 1 week 
 
if improved to grade 1 or baseline in 1 week, resume at reduced dose with LFT 
testing every week for 6 weeks; 

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 
if not, discontinue savolitinib. 
 
6.8.1.3 
Dose modifications due to other savolitinib-related toxicity  
Table 9 
Dose modifications for savolitinib-related toxicities 
NCI CTCAE toxicity grade 
Action 
Grade 0, 1, or 2 
None 
Grade 3a 
Hold savolitinib and follow the algorithm below: 
• 
Grade 3 toxicity for ≤7 days and resolves to 
≤Grade 2 or baseline within 14 days of onset 
• 
Toxicity persists at Grade 3 for >7 days 
• 
Resume dosing at same dose or one reduced 
dose level (maximum of 2 dose reductions) as 
clinically appropriate 
• 
Discontinue savolitinib 
Grade 4  
Follow the algorithm below: 
• 
Expected to be manageable/reversible with dose 
reduction  
• 
Not expected to be manageable/reversible with 
dose reduction 
• 
Hold dosing and consult with AstraZeneca 
study physician 
• 
Discontinue savolitinib 
Recurrence of Grade 3 
 
• 
Grade 3 toxicity for ≤7 days and resolves to 
≤Grade 2 or baseline within 14 days of onset 
• 
Grade 3 toxicity for >7 days 
• 
Resume dosing at same dose or one reduced 
dose level (maximum of 2 dose reductions) as 
clinically appropriate 
• 
Discontinue savolitinib 
Recurrence of Grade 4 
• 
Discontinue savolitinib 
No more than 2 dose reductions will be allowed for any patient.  Patients on 400 mg savolitinib due to weight <50 kg will 
only be allowed one dose reduction.  Patients requiring additional dose modifications due to toxicity will discontinue study 
treatment. 
a 
Despite appropriate supportive care   
 
 
 
 

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6.8.1.4 
Dose modifications for savolitinib-related QTcF prolongation 
Dose modifications for savolitinib-related QTcF prolongation are reported in Table 10 
Table 10 
Dose modifications for savolitinib-related QTcF prolongation  
NCI CTCAE toxicity grade 
Action 
Grade 0, 1, or 2 
None 
Grade 3 
Hold dosing and follow algorithm below  
• 
Patients with QTcF prolongation to >500 msec on 
at least two separate ECGs  
• 
If the toxicity does not resolve to QTcF <481msec 
within 21 days 
• 
Consult with a cardiologist to validate ECG 
finding. Ensure cardiac surveillance and take 
actions in accordance with clinical standard. 
Regular ECGs performed until resolution to 
QTcF <481 msec and then restart drug at 
one reduced dose level 
• 
Discontinue study drug and consult with a 
cardiologist for further management as 
clinically indicated   
Grade 4  
 
• 
QTcF ≥501 or >60 msec change from baseline 
and Torsades de pointes or polymorphic 
ventricular tachycardia or signs/symptoms of 
serious arrhythmia 
• 
Discontinue study drug and consult with a 
cardiologist for further management as 
clinically indicated 
 
6.8.1.5 
Risk minimisation activities for identified and potential risks associated with 
savolitinib 
The following section highlights risk minimisation activities for the key identified and 
potential risks identified in either preclinical studies or from ongoing clinical studies. 
Identified risks 
Liver Function Tests 
Drug-induced liver injury (DILI) is an AESI for savolitinib and requires specific monitoring. 
For more information see Section 6.1.1 or the most current version of the IB.  Weekly 
monitoring of liver function tests will be done for the first 9 weeks and then at the start of 
every cycle thereafter.  The hepatotoxicity management algorithm (Section 6.8.1.2) now 
clearly defines and limits the patients on savolitinib who can be re-challenged to those with 
lower grade abnormalities with rapid resolution.  As stated in the eligibility criteria and risk 
mitigation sections, patients with significantly abnormal baseline liver function tests will be 
excluded from the study.  In addition, as mentioned in Section 6.1.1, a 400-mg dose for 
patients below 50 kg will be used to potentially reduce the risk of hepatotoxicity. 
Pyrexia and hypersensitivity 
Pyrexia and hypersensitivity have been identified as a risk for patients receiving savolitinib. 
Pyrexia was followed in some cases by DILI (see above) or an association of symptoms 

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suggestive of hypersensitivity such as, but not limited to, allergic rash, cytopenias, 
myalgia/arthralgia 
  Patients who experience pyrexia with or without an 
association of the above symptoms after initiation of savolitinib treatment must follow the 
toxicity management guidelines. 
QTc prolongation 
 QTc interval prolongation potential of savolitinib 600mg was assessed in a thorough QT 
study in healthy volunteers. Analysis of the data concluded that it is a positive study as the 
upper two-sided 90% CI for the mean ΔΔQTcF was 13.6 and 14.0 msec at 4 and 5 hours, 
respectively. Regular ECG assessments will be done throughout the study according to the 
study plan. Patients who present ECG abnormalities with or without symptoms during 
treatment with savolitinib must follow the QTc prolongation toxicity management guidelines. 
Oedema  
Peripheral oedema has been observed in patients receiving savolitinib.  These events have 
been Grade 1 or 2, and the incidence does not appear to be dose related.  Oedema has also 
been observed with other MET inhibitors including onartuzumab and crizotinib.  Oedema 
should be monitored by clinical examination and measurement of weight.  Diuretic therapy 
should be considered at the discretion of the investigator.  Renal function will be carefully 
monitored.  
Nausea/vomiting 
Nausea and/or vomiting are common causally related AEs seen in clinical trials of savolitinib.  
If vomiting occurs after taking savolitinib, the patient should be instructed not to retake the 
dose.  Patients should take the next scheduled dose of savolitinib.  Patient reports of nausea 
and vomiting are expected to be evaluated and treated by investigators according to local 
practice (eg, use of antiemetic therapy, intravenous fluid replacement). 
Fatigue 
Fatigue is one of the more common causally related AEs seen in clinical trials of savolitinib. 
Follow the general guidance in the protocol for dose interruptions/reductions/ discontinuations 
as per Section 6.8.1. 
Potential risks 
Phototoxicity and/or rash 
Results of an in vitro (3T3) test suggest the potential for phototoxicity.  Measures to prevent 
photosensitivity have been included in ongoing studies.  There have been no reported cases of 
photosensitive rash.  Adverse events of Grade 1 rash, erythema and pruritus have been 
reported in some patients.  During savolitinib therapy and for 4 weeks after the last dose, 
patients should be advised to avoid prolonged exposure to sun, wear protective clothing and a 

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hat and seek shade from the sun as far as possible; in addition, an SPF30+ sunscreen should be 
used.  Exposure to other sources of UV light including sunbeds, tanning booths, etc. should be 
avoided.  If sunburn occurs, it is important to discontinue the study medication and take action 
under the direction of a doctor.  Keeping the area of skin eruption moist and applying wet 
dressings may help relieve the symptoms.  Reactions may last a few days, however severe 
reactions may last up to a few weeks.  Topical steroid creams may be helpful in treating the 
redness, and antihistamines are generally helpful in minimizing the itching.  In severe cases, a 
short course (10-14 days) of oral steroids, under the direction of a doctor, can be used.  
Testicular toxicity 
In the 3-month GLP dog study, histopathological findings were seen in the testes 
(seminiferous tubular degeneration) and/or epididymides (cellular debris, reduced 
cellularity/sperm) at all doses levels.  Group mean exposures in male dogs at the lowest 
observed effect level (LOEL) were approximately 4-fold above the group mean AUC in 
patients at the 600 mg QD dose (17.06 µg/mL).  A no observed effect level (NOEL) was not 
identified for the testicular/epididymal findings.  Reversibility was not assessed in this study, 
but lesions of this nature and severity (minimal to mild) would be expected to recover given 
sufficient time off-dose.   
Male patients taking savolitinib must use a condom during sexual intercourse with a female 
partner of childbearing potential (pregnant or not) and refrain from donating sperm during the 
study and for 6 months after their last dose. 

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6.8.2 
Management of sunitinib-related toxicities 
Table 11 
Dose modifications for sunitinib-related toxicities (including hepatic) 
NCI CTCAE toxicity grade 
Action 
Grade 0, 1, or 2 
None 
Grade 3a 
Hold sunitinib and follow the algorithm below: 
• 
Toxicity at Grade 3 for ≤7 days and resolves 
to ≤Grade 1 or baseline 
• 
Toxicity persists at Grade 3 for >7 days 
• 
Resume dosing at one reduced dose level 
(maximum of 2 dose reductions) 
• 
Discontinue sunitinib 
Grade 4  
Follow the algorithm below: 
• 
Expected to be manageable/reversible with 
dose reduction  
• 
Not expected to be manageable/reversible 
with dose reduction 
• 
Hold dosing and consult with AstraZeneca study 
physician 
• 
Discontinue sunitinib 
Recurrence of Grade 3 
 
• 
Grade 3 toxicity for ≤7 days and resolves to 
≤Grade 1 or baseline  
• 
Grade 3 toxicity for >7 days 
• 
Resume dosing at one reduced dose level 
(maximum of 2 dose reductions) 
• 
Discontinue sunitinib 
Recurrence of Grade 4 
• 
Discontinue sunitinib 
No more than 2 dose reductions will be allowed for any patient.  Patients on 400 mg savolitinib due to weight 
<50 kg will only be allowed one dose reduction.  Patients requiring additional dose modifications due to toxicity 
will discontinue study treatment. 
a 
Despite appropriate supportive care   
 
6.8.2.1 
Risk minimisation activities for risks associated with sunitinib 
Adrenal function:  Physicians prescribing SUTENT are advised to monitor for adrenal 
insufficiency in patients who experience stress such as surgery, trauma or severe infection. 
Dermatologic:  Severe cutaneous reactions have been reported with sunitinib, including cases 
of erythema multiforme (EM), Stevens-Johnson syndrome (SJS), and toxic epidermal 
necrolysis (TEN), some of which were fatal.  If signs or symptoms of SJS, TEN, or EM (eg, 
progressive skin rash often with blisters or mucosal lesions) are present, sunitinib should be 
discontinued.  If a diagnosis of SJS or TEN is suspected, sunitinib must not be re-started. 
Hepatic:  Sunitinib has been associated with hepatotoxicity, which may result in liver failure 
or death.  Liver failure has been observed in clinical trials (7/2281 [0.3%]) and post-marketing 
experience.  Liver failure signs include jaundice, elevated transaminases and/or 
hyperbilirubinemia in conjunction with encephalopathy, coagulopathy, and/or renal failure. 
Sunitinib should be interrupted for Grade 3 or 4 drug-related hepatic adverse events and 
discontinued if there is no resolution.  Do not restart sunitinib if patients subsequently 
experience severe changes in liver function tests or have other signs and symptoms of liver 
failure. 

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Hypertension:  Patients should be monitored for hypertension and treated as needed with 
standard anti-hypertensive therapy.  Interruption and re-initiation at a reduced dose should be 
implemented as per Table 8.  Grade 3 hypertension (>160/100, more intensive therapy than 
was previously used indicated) was observed in 50/375 treatment-naïve RCC patients (13%) 
on sunitinib. Severe hypertension (>200 mmHg systolic or 110 mmHg diastolic) occurred in 
32/375 treatment-naïve RCC patients (9%) on sunitinib.   
Hypoglycaemia:  Sunitinib has been associated with symptomatic hypoglycemia, which may 
result in loss of consciousness, or require hospitalisation.  Hypoglycemia has occurred in 
clinical trials in 2% of the patients treated with sunitinib for RCC. Reductions in blood 
glucose levels may be worse in diabetic patients.  Check blood glucose levels regularly during 
and after discontinuation of treatment with sunitinib.  Assess if anti-diabetic drug dosage 
needs to be adjusted to minimise the risk of hypoglycemia. 
Infections:  Necrotizing fasciitis, including fatal cases, has been reported in patients treated 
with sunitinib, including of the perineum and secondary to fistula formation.  Discontinue 
sunitinib in patients who develop necrotizing fasciitis. 
Myocardial dysfunction/CHF:  Patients should be carefully monitored for clinical signs or 
symptoms of congestive heart failure.  Blood pressure should be monitored and managed 
promptly.  In the presence of clinical manifestations of congestive heart failure (CHF), 
sunitinib should be discontinued.  The dose should be interrupted and/or reduced in patients 
without clinical evidence of CHF but with an ejection fraction <50% and >20% below 
baseline.  
Pancreatitis: Pancreatitis was observed in 5 (1%) patients receiving sunitinib for treatment-
naïve RCC compared to 1 (<1%) patient receiving IFN-α. If symptoms of pancreatitis are 
present, patients should discontinue sunitinib. 
Proteinuria: Interrupt treatment for 24-hour urine protein ≥3 grams and dose reduce. 
Discontinue for nephrotic syndrome or repeat episodes of protein ≥3 grams/24 hours despite 
dose reductions.  
Thyroid Dysfunction:  Patients should be observed closely for signs and symptoms of 
thyroid dysfunction, including hypothyroidism, hyperthyroidism, and thyroiditis, on sunitinib 
treatment.  All patients should have monitoring of thyroid function performed as per Table 1 
and be treated as per standard medical practice.  
Tumour Lysis Syndrome (TLS):  Cases of TLS, some fatal, have been observed in patients 
treated with sunitinib.  Patients generally at risk of TLS are those with high tumour burden 
prior to treatment.  These patients should be monitored closely and treated as clinically 
indicated. 

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Thrombotic Microangiopathy (TMA):  Thrombotic microangiopathy including thrombotic 
thrombocytopenic purpura and hemolytic uremic syndrome, sometimes leading to renal failure 
or a fatal outcome, has been reported in patients treated with sunitinib.  Discontinue sunitinib 
in patients developing TMA.  Reversal of the effects of TMA has been observed after 
treatment was discontinued. 
Wound healing:  Cases of impaired wound healing have been reported during sunitinib 
therapy.  Temporary interruption of sunitinib therapy is recommended for precautionary 
reasons in patients undergoing major surgical procedures.  There is limited clinical experience 
regarding the timing of reinitiation of therapy following major surgical intervention. 
Therefore, the decision to resume sunitinib therapy following a major surgical intervention 
should be based upon clinical judgment of recovery from surgery. 
7. 
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS 
7.1 
Identity of study medications 
AstraZeneca will supply savolitinib tablets for oral use.  The tablets will be supplied in the 
200-mg strength, in open-labelled high-density polyethylene (HDPE) bottles.  Additional 
information about the investigational product may be found in the IB. 
Sunitinib will be sourced locally in US and dispensed by the sites.  In other countries, 
Sunitinib will be packed, labelled and distributed by AZ through the IVRS/IWRS. 
Sunitinib will be the commercial carton supplied by Pfizer.  The original carton will be the 
labelled with a clinical study label and contain the original blister packs and English language 
patient information leaflet. 
Table 12  
IP strength and manufacturer 
Investigational product 
Dosage form and strength 
Manufacturer 
Savolitinib 
200 mg tablets 
AstraZeneca, Sweden 
Sunitinib   
 25 mg & 12.5 mg capsules 
Pfizer 
 
7.2 
Dose and treatment regimens 
7.2.1 
Savolitinib 
Savolitinib will be dosed as follows: 
For patients ≥50 kg at the start of treatment, savolitinib 600 mg PO QD, and for patients 
<50 kg at the start of treatment, savolitinib 400 mg PO QD will be administered in 42-day 
(6-week) treatment cycles. 

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Savolitinib is to be administered with a meal.  The time of day for administration of 
savolitinib should be consistent and the actual time the dose is taken should be recorded in the 
eDiary each day.  
On scheduled PK collection days and clinic visit days the patient should be instructed to wait 
until he/she arrives at the study centre to take their study medication with a meal when 
instructed. 
If the patient misses a dose of study medication, the patient should take the dose as soon as 
possible, but not less than 12 hours before the next dose is due.  
If vomiting occurs after taking the study medication, the patient should be instructed not to 
retake the dose.  Patients should take the next scheduled dose of savolitinib.  If vomiting 
persists, the patient should contact the investigator.  Ondansetron or another serotonin-
receptor antagonist may be used.   
Patients should be instructed to bring any unused savolitinib in the original bottles, in addition 
to returning any empty bottles to each clinic visit.  Savolitinib dosing compliance/drug diary 
should be reviewed with the patient at each clinic visit, including the visit at the beginning of 
each cycle when study medication is dispensed.   
7.2.2 
Sunitinib 
Sunitinib:  two 25 mg capsules PO QD, with or without food will be administered in 6-week 
treatment cycles: 4 weeks on/2 weeks off. 
The time of day for administration of sunitinib should be consistent and the actual time the 
dose is taken should be recorded in the eDiary each day.  
If the patient misses a dose of study medication, it should be taken as soon as it is 
remembered.  A missed dose should not be taken, though, if it is close to the next dose. In this 
case, the next dose should be taken at the regular time.  More than 1 dose of sunitinib should 
not be taken at a time. 
 If vomiting occurs after taking sunitinib, the patient should be instructed not to retake the 
dose.  Patients should take the next scheduled dose of sunitinib.  If vomiting persists, the 
patient should contact the investigator.  Ondansetron or another serotonin-receptor antagonist 
may be used.   
On clinic visit days the patient should be instructed to wait until he/she arrives at the study 
centre to take their study medication when instructed. 
Patients should be advised to bring any unused sunitinib in the original blister packs, in 
addition to returning any empty blister packs to each clinic visit.  Sunitinib dosing compliance 

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should be reviewed with the patient at each clinic visit, including the visit at the beginning of 
each cycle when study medication is dispensed.   
7.3 
Labelling 
Labels will be prepared in accordance with Good Manufacturing Practice (GMP) and local 
regulatory guidelines.  The labels will fulfil GMP Annex 13 requirements for labelling, where 
applicable for that country.  Label text will be translated into local language. 
7.4 
Storage 
All study medications should be kept in a secure place under appropriate storage conditions.  
The investigational product label on the pack specifies the appropriate storage. 
7.5 
Compliance 
The administration of study medications should be recorded in the appropriate sections of the 
eCRF.  Treatment compliance will be assessed by the tablet or capsule count and the 
information should be recorded in the appropriate section of the eCRF. 
An eDiary will be provided to all patients.  Patients will be asked to record the date and time 
of their self-administered doses in the eDiary on all study days in order to monitor compliance 
and aid in PK data interpretation for those taking savolitinib.  
7.6 
Accountability 
The study medications provided for this study will be used only as directed in the Clinical 
Study Protocol.  Details of treatment with investigational product for each patient will be 
recorded in the eCRF. 
Patients must return all unused medication and medication containers to the clinic at the time 
of every visit for a pill count and reconciliation with the eDiary. 
The study site staff at the investigational site will account for all drugs dispensed and returned 
and for appropriate destruction.  Certificates of delivery, destruction and return must be 
signed.  
7.7 
Concomitant and other treatments  
7.7.1 
Permitted concomitant medications and treatments 
Blood transfusions are allowed during the study. 
Patients are permitted to receive granulocyte colony stimulating factor (G-CSF) or 
granulocyte-macrophage colony stimulating factor (GM-CSF) in accordance with the 
American Society of Clinical Oncology’s (ASCO) guidelines 

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Patients may receive bisphosphonates and/or RANK ligand inhibitors like denosumab, or 
corticosteroids for the treatment of bone metastases.  However, patients receiving sunitinib 
should avoid invasive dental procedures if they have ever received bisphosphonates.  Any 
patient who has received bisphosphonates requires a maxillofacial exam prior to 
randomisation (see Table 1). 
Limited field palliative radiotherapy may be used for the treatment of pain at the site of bony 
metastases that were present at baseline, provided the investigator does not feel that these are 
indicative of clinical disease progression during the study period.   
7.7.2 
Restrictions based on clinical pharmacology for both study medications 
Refer to Appendix H for concomitant medications that should be restricted or used with 
caution. 
Patients who have taken strong inducers or inhibitors of CYP3A4 or strong inhibitors of 
CYP1A2 within 2 weeks of randomisation are excluded from the trial.  Herbal medications 
cannot be taken within 7 days of randomisation (3 weeks for St John’s wort) or throughout the 
course of the study.  
Savolitinib-specific restrictions based on clinical pharmacology  
 
Savolitinib is a weak inhibitor of OATP1B1, OATP1B3 and BCRP.  Discontinuation of 
statins is advised unless considered essential, in which case, the patient should be 
prescribed the lowest available dose and monitored for the effects of increased statin 
exposure.   
 
Savolitinib and its major metabolite, M2, are weak competitive inhibitors of CYP2C8 
(IC50=
 and 
 μM, respectively).  Those drugs defined as strong CYP2C8 substrates 
(almost exclusively metabolised by CYP2C8, such as Repaglinide and Rosiglitazone) 
should be used with caution.  
 
Savolitinib and its major metabolite, M2, are weak competitive inhibitors of CYP3A4/5 
(IC50 = 
 and 
 μM, respectively).  Concomitant use of CYP3A4 substrates which 
have a narrow therapeutic range or CYP3A4 sensitive substrates during the trial should be 
avoided as far as possible unless considered essential by the investigator, in which case 
patients must be monitored closely for potentially increased toxicity due to drug-drug 
interactions. 
 
Savolitinib is not a substrate of P-glycoprotein (Pgp) but is a weak inhibitor in vitro 
(IC50=
μM).  Drugs that are known to be affected by Pgp such as digoxin, quinidine, 
loperamide, saquinavir and ritonavir should be used with caution.  
 
Savolitinib is an inhibitor of MATE1 and MATE2K (IC50 
  Metformin should be 
used with caution and patients monitored for the effect of increased metformin exposure. 
 

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7.7.3 
Other concomitant treatment 
Other medication other than that described above, which is considered necessary for the 
patient’s safety and wellbeing, may be given at the discretion of the investigator and recorded 
in the appropriate sections of the Case Report Form. 
8. 
STATISTICAL ANALYSES BY ASTRAZENECA 
8.1 
Statistical considerations 
A comprehensive Statistical Analysis Plan (SAP) will be prepared prior to the first subject 
randomised and any subsequent amendments will be documented, with final amendments 
completed prior to database lock.  The aim of this study is to compare the efficacy and safety 
of savolitinib versus sunitinib.  Analyses will be performed by AstraZeneca or its 
representatives.  All personnel involved with the analysis of the study will remain blinded to 
aggregated results until database lock and protocol violators identified. 
Due to termination of recruitment into SAVOIR, all secondary analyses will be descriptive. 
Sample size estimate 
Approximately 180 patients were planned to be randomised from 5 to 10 countries worldwide 
in approximately 50 to 75 sites.  Recruitment to the study was closed on 22 November 2018.  
It is now estimated that approximately 50 patients will be randomised from 7 countries. 
The initial assumption was that the true treatment effect had a hazard ratio (HR) of 0.6 (which 
would have translated to an approximate 3-month improvement in median PFS over an 
assumed 4-month median PFS for MET-driven patients on sunitinib, assuming PFS was 
exponentially distributed), 121 PFS events confirmed by BICR would have had to have been 
observed for the study to have 80% power to show a statistically significant difference in PFS 
at the two-sided 5% level.  The smallest treatment difference that would have been statistically 
significant at the final analysis was a PFS HR of 0.69.  Assuming 67% maturity; 180 patients 
would have been needed to be randomised.  An interim futility analysis of PFS was planned to 
be conducted when a total of approximately 36 BICR-confirmed PFS events had been 
observed (30% of 121 PFS events, which was estimated to occur 17 months after the first 
patient had been randomised).  Following IDMC endorsement to terminate recruitment into 
SAVOIR, the interim analysis will not occur. 
 
 
 
 
  
 

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Following IDMC endorsement to terminate recruitment into SAVOIR, a sample 
size-reassessment will no longer be performed. 
8.2 
Definitions of analysis sets 
8.2.1 
Full analysis set 
The full analysis set (FAS) will include all randomised patients and will compare the 
treatment groups on the basis of randomised treatment, regardless of the treatment actually 
received.  Patients who were randomised but did not subsequently go on to receive study 
treatment are included in the ITT population.  Therefore, all efficacy and HRQoL data will be 
summarised and analysed using the FAS on an ITT basis.  
8.2.2 
Safety analysis set 
The safety analysis set consists of all patients who received at least one dose of randomised 
treatment (regardless of whether that was the randomised therapy intended or indeed whether, 
in rare cases, they received therapy without being randomised), according to the treatment 
they actually received.  PRO CTCAE data will be summarised using the SAS. 
8.2.3 
PK analysis set 
All patients who receive at least 1 dose of savolitinib per the protocol, for whom any post-
dose PK data are available and do not violate or deviate from the protocol in ways that would 
significantly affect the PK analyses will be included in the PK analysis set.  The population 
will be defined by the Study Team Physician, Pharmacokineticist and Statistician prior to any 
analyses being performed.  Where a protocol deviation impacts only part of a subject’s data, 

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the affected portion of the subject’s PK data will be excluded from PK analysis and summary 
statistics, and the remaining valid data will be utilised.  
8.3 
Outcome measures for analyses 
8.3.1 
 Calculation or derivation of efficacy variables 
8.3.1.1 
Blinded Independent Central Review (BICR) of RECIST-based assessments 
Review of radiological imaging data will be carried out using RECIST version 1.1.  All 
imaging assessments including unscheduled visit scans will be collected on an ongoing basis 
and sent to the sponsor-designated vendor by the site following completion of each scan.  All 
scans will be read by BICR after notification of Progressive Disease by the investigator.  If PD 
is not centrally confirmed, each subsequent scan will be read by BICR once it is received and 
processed by the sponsor-designated vendor.  Once the institution calls PD, the scans will be 
reviewed by two independent radiologists using RECIST 1.1 criteria and will be adjudicated if 
required.  The radiologists will be blinded to treatment.  Depending on the speed and 
completeness of image submission to the sponsor-designated vendor, the turn-around time 
should generally be within 10 days.  All scans will be reviewed for the primary analysis even 
for the patients who do not have PD per local review. 
For each patient, BICR will define the overall visit response data (CR, PR, SD, PD or NE) and 
the relevant scan dates for each time point (ie, for visits where response or progression is/is 
not identified).  If a patient has had a tumour assessment which cannot be evaluated, then the 
patient will be assigned a visit response of not evaluable (NE).  
8.3.1.2 
Progression-Free Survival (PFS) 
PFS is defined as the time from randomisation until the date of objective disease progression 
or death (by any cause in the absence of progression), regardless of whether the subject 
withdraws from randomised therapy or receives another anti-cancer therapy prior to 
progression.  Patients who have not progressed or died at the time of analysis will be censored 
at the time of the latest date of assessment from their last evaluable RECIST assessment. 
However, if the patient progresses or dies after two or more missed visits, the patient will be 
censored at the time of the latest evaluable RECIST assessment prior to the two missed visits.  
The PFS time will always be derived based on scan/assessment dates not visit dates. 
RECIST assessments/scans contributing towards a particular visit may be performed on 
different dates. The following rules will be applied: 
 
Date of progression will be determined based on the earliest of the dates of the component 
that triggered the progression. 
 
When censoring a patient for PFS the patient will be censored at the latest of the dates 
contributing to a particular overall visit assessment. 

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The primary analysis of PFS will be based on BICR; PFS per investigator review will be a 
sensitivity analysis. 
8.3.1.3 
Objective Response Rate (ORR) 
ORR rate is defined as the number (%) of patients with measurable disease with at least one 
visit response of CR or PR. Data obtained up until progression, or last evaluable assessment in 
the absence of progression, will be included in the assessment of ORR.  However, any 
complete response or partial response, which occurred after a further anticancer therapy was 
received, will not be included in the numerator for the ORR calculation. 
Summaries of ORR will be based on BICR; ORR per investigator review will be a sensitivity 
analysis. 
8.3.1.4 
Duration of Response (DoR) 
Duration of response will be defined as the time from the date of first documented response on 
study medication until the date of BICR-confirmed progression or death in the absence of 
disease progression.  The end of the duration of response should coincide with the date of 
progression or death from any cause used for the PFS endpoint.  The time of the initial 
response will be defined as the latest of the dates contributing towards the first visit response 
of PR or CR.  If a patient does not progress following a response, then their duration of 
response will use the PFS censoring time. 
Summaries of DoR will be based on BICR; DoR per investigator review will be a sensitivity 
analysis. 
8.3.1.5 
Disease control rate (DCR) 
Disease control rate at 6 months is defined as the percentage of patients who have a best 
objective response of CR or PR in that period or who have demonstrated SD for a minimum 
interval of 24 weeks (minus 1 week to allow for an early assessment within the assessment 
window, ie, 161 days) following the date of randomisation.  Disease control rate at 12 months 
is defined as the percentage of patients who have a best objective response of CR or PR in that 
period or who have demonstrated SD for a minimum interval of 48 weeks (minus 1 week to 
allow for an early assessment within the assessment window, ie, 329 days) following the date 
of randomisation. 
Summaries of DCR will be based on BICR; DCR per investigator review will be a sensitivity 
analysis. 
8.3.1.6 
Tumour shrinkage 
Tumour shrinkage will be assessed using RECIST tumour response.  The absolute change and 
percentage change from baseline in sum of tumour size at each assessment will be calculated. 

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The best change in tumour size will include all assessments prior to progression or start of 
subsequent anticancer therapy. 
Summaries of tumour shrinkage will be based on BICR; tumour shrinkage per investigator 
review will be a sensitivity analysis. 
8.3.1.7 
Overall Survival (OS) 
OS is defined as the time from the date of randomisation until death due to any cause.  Any 
patient not known to have died at the time of analysis will be censored based on the last 
recorded date on which the patient was known to be alive. 
Note:  Survival calls will be made within 5 days following the date of the data cut-off for each 
OS analysis, and if patients are confirmed to be alive, or if the death date is post the final data 
cut-off date, these patients will be censored at the date of the final data cut off.  Death dates 
may be found by checking publicly available death registries. 
8.3.1.8 
Time to second progression or death (PFS2) 
Time from randomisation to second progression or death is defined as the time from the date 
of randomisation to either the progression event after the start of a subsequent non-study 
anti-cancer therapy, or death.  Determination of PD for second PFS on subsequent anti-cancer 
therapy will only be collected in those patients who had PD by RECIST 1.1 on study 
medication (investigator assessed).  The date of second progression will be recorded by the 
investigator and defined according to local standard clinical practice.  The date of each scan 
evaluating tumour response on subsequent therapy and the investigator opinion of progression 
status (progressed or non-progressed) at each assessment will be recorded in the electronic 
case report form (eCRF).  The site staff should review second progression status and record all 
subsequent therapy at least every 12 weeks following study medication discontinuation. 
Patients who are alive and for whom a second disease progression (PFS2) has not been 
observed should be censored at the last time known to be alive and without a second disease 
progression, ie, censored at the latest of the PFS or PFS2 assessment date if the patient has not 
had a second progression or death. 
8.3.1.9 
HRQoL and symptoms 
Patient reported outcomes will be assessed using the FACIT-F and FKSI-19 questionnaires. 
An outcome variable consisting of a score calculated using respective scoring manuals will be 
derived for each of the symptom scales/symptom items of these questionnaires.  Higher scores 
on the global health status and functioning scales indicate better health status/function.  
Higher scores on the symptoms scales indicate greater symptom burden (see Section 5.3.1 for 
more details). PRO-CTCAE will be analysed descriptively since it is an exploratory endpoint. 

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8.4 
Methods for statistical analyses 
All efficacy analyses will be performed on the FAS populations.  Results of all statistical 
analyses will be presented using a 95% confidence interval and 2-sided p-value. 
The below mentioned general principles will be followed throughout the study: 
 
Descriptive statistics will be used for all variables, as appropriate.  Continuous variables 
will be summarised by the number of observations, mean, standard deviation, median, 
minimum, and maximum. Categorical variables will be summarised by frequency counts 
and percentages for each category. 
 
Unless otherwise stated, percentages will be calculated out of the population total and for 
each treatment group. 
 
Baseline will be the last assessment of the variable under consideration prior to the intake of 
the first dose of investigational product, except for efficacy variables.  For efficacy variables, 
baseline is defined as the last visit prior to randomisation. 
Efficacy and HRQoL data will be summarised based upon the FAS analysis set. Safety and 
treatment exposure data will be summarised based upon the safety analysis set by actual 
treatment received.  Study population and demography data will be summarised based upon 
the FAS analysis set. 
8.4.1 
Analysis of the primary variable (s) 
The log-rank test will be stratified by IMDC risk group (poor, intermediate, favourable) and 
line of therapy (1st line; previously treated with an anti-VEGF TKI; previously treated without 
an anti-VEGF TKI) providing there are at least 10 PFS events within each strata.  If not, then 
the log-rank test will be stratified by IMDC risk group only, providing there are at least 
10 PFS events within each strata.  If not, then the log-rank test will be unstratified. 
The effect of treatment will be estimated by the HR together with its corresponding 95% CI 
and p-value.  Kaplan Meier plots will be provided. 
8.4.2 
Analysis of the secondary variable(s) 
Objective Response and Disease Control Rates 
ORR and DCR will be presented with a two-sided 95% CIs using Clopper-Pearson method 
(Clopper and Pearson, 1934).  The number and percentage of patients in each response 
category (CR, PR, SD, PD, NE) will be summarised.  Results may be summarised by the 
IMDC risk category if patient numbers permit. 
Duration of response 
Kaplan-Meier plots of duration of response in the responding patients will be produced. 

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Change in tumour size 
The best change in target lesion tumour size from baseline (where best change in target lesions 
size is the maximum reduction from baseline or the minimum increase from baseline in the 
absence of a reduction) will also be summarised. 
Waterfall plots (bar charts) indicating the best percentage change from baseline in sum of the 
diameters of TLs will be produced.  Reference lines at the +20% and 30% change in tumour 
size levels will be added to the plots, which correspond with the definitions of progression and 
‘complete or partial’ response respectively.   
Overall Survival  
Summaries (number of deaths, medians, and proportion alive at 1 year) and Kaplan Meier 
plots will be provided. 
Time to second progression or death (PFS2) 
Summaries (number of 2nd progression events or deaths, medians, and proportion alive at 
1 year) and Kaplan Meier plots will be provided. 
PRO analyses 
Analyses on the FACIT-F, FKSI-19, EQ-5D-5L and PRO-CTCAE will be based on the 
instruments’ scoring manuals. 
Descriptive statistics will be calculated for each scheduled visit/time point in the study, for 
each trial arm and as a total.  These will report the number of patients, the number of EQ-5D 
questionnaires completed at each visit, the number and proportion responding to each 
dimension of the EQ-5D-5L.  Additionally, summary statistics (eg, n, mean, median, sd, min, 
max) will be reported for the EQ-5D index score and the EQ-VAS score, and the change from 
baseline for the EQ-5D index score and the EQ-VAS score. 
To support submissions to payers, additional analyses may be undertaken and these will be 
outlined in a separate Payer Analysis Plan. 
Safety analyses 
Safety data will not be analysed formally.  Standard data summaries will be produced for 
safety data including (but not limited to): 
 
Summaries of AEs of any CTCAE grade – summarised by MedDRA preferred term and 
system organ class and CTCAE grade. 
 
Summaries of Grade 3 and above AEs. 
 
SAEs. 

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 
Any AE occurring within the defined 30 day follow up period after discontinuation of 
investigational product will be included in the AE summaries.   
 
Deaths will be summarised by primary cause, along with AEs with an outcome of “fatal”. 
 
Haematology, clinical chemistry, vital signs, ECG, ECHO/MUGA data and concomitant 
medication will be summarised. 
 
Any qualitative safety assessments for urinalysis will be presented as is deemed 
appropriate.  This may include, but is not restricted to, presentation of parameters against 
time, concentration, or shift plots.  Appropriate scatter plots will also be considered to 
investigate trends in parameters compared with baseline. 
 
8.4.3 
Subgroup analysis 
No subgroup analysis will be performed. 
8.4.4 
Interim analysis 
An interim futility analysis of PFS was planned to be conducted when a total of approximately 
36 PFS events confirmed by BICR had been observed (30% of 121 PFS events, which was 
estimated to occur 17 months after the first patient had been randomised).  Following IDMC 
endorsement to terminate recruitment into SAVOIR, the interim analysis will not occur. 
8.4.5 
Sensitivity analysis  
Investigator assessment:  
PFS will be reported per investigator assessment. 
8.4.6 
Exploratory analyses  
8.4.6.1 
 Pharmacokinetics 
The savolitinib plasma concentration data obtained from the samples collected in this study 
may be included in the listings of the CSR but these data will be pooled with data from other 
studies in order to perform a population PK analysis.  The results of this analysis will be 
reported in a separate population PK report. 
8.4.6.2 
Pharmacogenetic research and statistical methods, and determination of 
sample size  
The number of patients that will agree to participate in the genetic research is unknown.  It is 
therefore not possible to establish whether sufficient data will be collected to allow a formal 
statistical evaluation or whether only descriptive statistics will be generated.  A statistical 
analysis plan will be prepared where appropriate. 

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9. 
STUDY AND DATA MANAGEMENT BY ASTRAZENECA 
9.1 
Training of study site staff 
Before the first patient is entered into the study, an AstraZeneca representative will review and 
discuss the requirements of the Clinical Study Protocol and related documents with the 
investigational staff and also train them in any study specific procedures and the WBDC and 
ePRO systems utilised. 
The Principal Investigator will ensure that appropriate training relevant to the study is given to 
all of these staff, and that any new information relevant to the performance of this study is 
forwarded to the staff involved. 
The Principal Investigator will maintain a record of all individuals involved in the study 
(medical, nursing and other staff). 
9.2 
Monitoring of the study 
During the study, an AstraZeneca representative will have regular contacts with the study site, 
including visits to: 
 
Provide information and support to the investigator(s). 
 
Confirm that facilities remain acceptable. 
 
Confirm that the investigational team is adhering to the Clinical Study Protocol, that data 
are being accurately and timely recorded in the eCRFs, that biological samples are 
handled in accordance with the Laboratory Manual and that study medication 
accountability checks are being performed. 
 
Perform source data verification (a comparison of the data in the eCRFs with the patient’s 
medical records at the hospital or practice, and other records relevant to the study) 
including verification of informed consent of participating patients. This will require 
direct access to all original records for each patient (eg, clinic charts). 
 
Ensure withdrawal of informed consent to the use of the patient’s biological samples is 
reported and biological samples are identified and disposed of/destroyed accordingly, and 
the action is documented, and reported to the patient. 
 
The AstraZeneca representative will be available between visits if the investigator(s) or other 
staff at the centre needs information and advice about the study conduct. 
9.2.1 
Source data 
Refer to the Clinical Study Agreement (CSA) for location of source data. 

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9.2.2 
Study agreements 
The Principal Investigator at each centre should comply with all the terms, conditions, and 
obligations of the Clinical Study Agreement (CSA), or equivalent, for this study.  In the event 
of any inconsistency between this Clinical Study Protocol and the CSA, the terms of Clinical 
Study Protocol shall prevail with respect to the conduct of the study and the treatment of 
patients and in all other respects, not relating to study conduct or treatment of patients, the 
terms of the Clinical Study Agreement shall prevail. 
Agreements between AstraZeneca and the Principal Investigator should be in place before any 
study-related procedures can take place, or patients are enrolled. 
9.2.3 
Archiving of study documents 
The Investigator follows the principles outlined in the CSA. 
9.3 
Study timetable and end of study 
The end of the study is defined as ‘the last clinic visit of the last subject undergoing the study’. 
The final analysis of all endpoints will be conducted at the earliest time when the following 
2 criteria are met: 
1 
36 PFS events by investigator assessment 
2 
The opportunity to have at least 7.5 months follow-up from randomisation 
 
If criterion #1 has not been met 12 months after last subject in, the final analysis will be 
performed. 
At this time point, the clinical study database will close to new data. 
The study may be terminated at individual centres if the study procedures are not being 
performed according to GCP, or if recruitment is slow.  AstraZeneca may also terminate the 
entire study prematurely if concerns for safety arise within this study or in any other study 
with savolitinib. 
9.4 
Data management by AstraZeneca  
Data management will be performed by AstraZeneca Data Management Centre according to 
the Data Management Plan.  The data collected through third party sources will be obtained 
and reconciled against study data. 
Adverse events and medical/surgical history will be classified according to the terminology of 
the latest version the Medical Dictionary for Regulatory Activities (MedDRA).  Medications 

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will be classified according to the WHO Drug Dictionary.  All coding will be performed by 
the Medical Coding Team at the AstraZeneca Data Management Centre.  
Data queries will be raised for inconsistent, impossible or missing data.  All entries to the 
study database will be available in an audit trail. 
The data will be validated as defined in the Data Management Plan.  Quality control 
procedures will be applied to each stage of data handling to ensure that all data are reliable 
and have been processed correctly.  The Data Management Plan will also clarify the roles and 
responsibilities of the various functions and personnel involved in the data management 
process. When all data have been coded, validated, and locked, clean file will be declared.   
9.4.1 
Serious Adverse Event (SAE) reconciliation 
SAE reconciliation reports are produced and reconciled with the Patient Safety database 
and/or the investigational site.  
9.4.2 
Data management of genotype data 
Any genotype data generated in this study will be stored in the AstraZeneca genotyping LIMS 
database, or other appropriate secure system within AstraZeneca and/or third party contracted 
to work with AstraZeneca to analyse samples.  The results from this genetic research may be 
reported in the CSR for the main study, or in a separate report as appropriate. 
Some or all of the clinical datasets from the main study may be merged with the genetic data 
in a suitable secure environment separate from the clinical database. 
9.4.3 
Data associated with human biological samples 
Data associated with biological samples will be transferred from laboratory(ies) internal or 
external to AstraZeneca. 
9.4.4 
Management of external data 
Data Management determines the format of the data to be received from external providers 
and coordinates the flow of data to an external environment or clinical database (if 
applicable).  Data Management will ensure that the data collection tool (eg, eDiary, 
IVRS/IWRS, etc.) will be tested/validated as needed. Data from external providers will be 
validated as appropriate to ensure it is consistent with the clinical data and included in the 
final database. 
In the case of 
data, the results of 
any analyses will not be recorded in the database, but information relating to the processing of 
the sample, including the original date of 
 and the 
actual date the sample(s) were collected) will be recorded in the eCRF and database. 

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10. 
ETHICAL AND REGULATORY REQUIREMENTS 
10.1 
Ethical conduct of the study 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with ICH/Good Clinical Practice, applicable 
regulatory requirements and the AstraZeneca policy on Bioethics and Human Biological 
Samples. 
10.2 
Patient data protection 
The Informed Consent Form will incorporate (or, in some cases, be accompanied by a 
separate document incorporating) wording that complies with relevant data protection and 
privacy legislation. 
AstraZeneca will not provide individual genotype results to patients, any insurance company, 
any employer, their family members, general physician, unless required to do so by law. 
Precautions are taken to preserve confidentiality and prevent genetic data being linked to the 
identity of the patient.  In exceptional circumstances, however, certain individuals might see 
both the genetic data and the personal identifiers of a patient. For example, in the case of a 
medical emergency, an AstraZeneca Physician or an investigator might know a patient’s 
identity and also have access to his or her genetic data.  Also, Regulatory authorities may 
require access to the relevant files, though the patient’s medical information and the genetic 
files would remain physically separate. 
10.3 
Ethics and regulatory review 
An Ethics Committee (EC) or Institutional Review Board (IRB) should approve the final 
Clinical Study Protocol, including the final version of the Informed Consent Form and any 
other written information and/or materials to be provided to the patients.  The investigator will 
ensure the distribution of these documents to the applicable EC/IRB, and to the study site 
staff. 
The opinion of the EC/IRB should be given in writing.  The investigator should submit the 
written approval to AstraZeneca before enrolment of any patient into the study.  
The EC/IRB should approve all advertising used to recruit patients for the study. 
AstraZeneca should approve any modifications to the Informed Consent Form that are needed 
to meet local requirements. 
If required by local regulations, the Clinical Study Protocol should be re-approved by the 
EC/IRB annually. 

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Before enrolment of any patient into the study, the final Clinical Study Protocol, including the 
final version of the Informed Consent Form, is approved by the national regulatory authority 
or a notification to the national regulatory authority is done, according to local regulations. 
AstraZeneca will handle the distribution of any of these documents to the national regulatory 
authorities. 
AstraZeneca will provide Regulatory Authorities, ECs/IRBs and Principal Investigators with 
safety updates/reports according to local requirements. 
Each Principal Investigator is responsible for providing the ECs/IRBs with reports of any 
serious and unexpected adverse drug reactions from any other study conducted with the 
investigational product.  AstraZeneca will provide this information to the Principal 
Investigator so that he/she can meet these reporting requirements. 
10.4 
Informed consent 
The Principal Investigator(s) at each centre will: 
 
Ensure each patient is given full and adequate oral and written information about the 
nature, purpose, possible risk and benefit of the study. 
 
Ensure each patient is notified that they are free to discontinue from the study at any time. 
 
Ensure that each patient is given the opportunity to ask questions and allowed time to 
consider the information provided. 
 
Ensure that each patient provides signed and dated informed consent before conducting 
any procedure specifically for the study. 
 
Ensure the original, signed Informed Consent Forms are stored in the Investigator’s Study 
File. 
 
Ensure a copy of the signed Informed Consent Form is given to the subject. 
 
Ensure that any incentives for patient who participate in the study as well as any 
provisions for patients harmed as a consequence of study participation are described in 
the informed consent form that is approved by an Ethics Committee or Institutional 
Review Board. 
 
The genetic research is optional, in countries where applicable, and the patient may participate 
in the main study without participating in the genetic component.  To participate in the genetic 
component of the study the patient must sign and date both the consent form for the main 
study (non-genetic components of the study) and the genetic component of the study.  Copies 
of both signed and dated consent forms must be given to the patient and the original filed at 
the study centre.  The Principal Investigator is responsible for ensuring that consent is given 
freely and that the patient understands that they may freely discontinue the genetic aspect of 
the study at any time. 

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10.5 
Changes to the Clinical Study Protocol and Informed Consent 
Form 
Study procedures will not be changed by AstraZeneca without consulting of the International 
Co-ordinating Investigator. 
If there are any substantial changes to the Clinical Study Protocol, then these changes will be 
documented in a new version of the study protocol. 
The new version of the Clinical Study Protocol is to be approved by the relevant Ethics 
Committee or Institutional Review Board and if applicable, also by the national regulatory 
authority, before implementation.  Local requirements are to be followed for new versions of 
Clinical Study Protocols. 
AstraZeneca will distribute any new versions of the Clinical Study Protocol to each Principal 
Investigator(s).  For distribution to Ethics Committee/Institutional Review Board see 
Section 10.3. 
If amended change to a Clinical Study Protocol requires a change to a centre’s Informed 
Consent Form, AstraZeneca and the centre’s Ethics Committee/Institutional Review Board are 
to approve the revised Informed Consent Form before the revised form is used.  
10.6 
Audits and inspections 
Authorised representatives of AstraZeneca, a regulatory authority, or an Ethics Committee 
may perform audits or inspections at the centre, including source data verification.  The 
purpose of an audit or inspection is to systematically and independently examine all 
study-related activities and documents, to determine whether these activities were conducted, 
and data were recorded, analysed, and accurately reported according to the Clinical Study 
Protocol, Good Clinical Practice (GCP), guidelines of the International Conference on 
Harmonisation (ICH), and any applicable regulatory requirements.  The investigator will 
contact AstraZeneca immediately if contacted by a regulatory agency about an inspection at 
the centre. 

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11. 
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Appendix A Additional Safety Information 
Further Guidance on the Definition of a Serious Adverse Event (SAE) 
Life threatening 
‘Life-threatening’ means that the patient was at immediate risk of death from the AE as it 
occurred or it is suspected that use or continued use of the product would result in the patient’s 
death.  ‘Life-threatening’ does not mean that had an AE occurred in a more severe form it 
might have caused death (eg, hepatitis that resolved without hepatic failure). 
Hospitalisation 
Outpatient treatment in an emergency room is not in itself a serious AE, although the reasons 
for it may be (eg, bronchospasm, laryngeal oedema).  Hospital admissions and/or surgical 
operations planned before or during a study are not considered AEs if the illness or disease 
existed before the patient was enrolled in the study, provided that it did not deteriorate in an 
unexpected way during the study. 
Important medical event or medical intervention 
Medical and scientific judgement should be exercised in deciding whether a case is serious in 
situations where important medical events may not be immediately life threatening or result in 
death, hospitalisation, disability or incapacity but may jeopardise the patient or may require 
medical intervention to prevent one or more outcomes listed in the definition of serious.  
These should usually be considered as serious. 
Simply stopping the suspect drug does not mean that it is an important medical event; medical 
judgement must be used. 
• 
Angioedema not severe enough to require intubation but requiring i.v. hydrocortisone 
treatment. 
• 
Hepatotoxicity caused by paracetamol (acetaminophen) overdose requiring treatment with 
N-acetylcysteine. 
• 
Intensive treatment in an emergency room or at home for allergic bronchospasm. 
• 
Blood dyscrasias (eg, neutropenia or anaemia requiring blood transfusion, etc.) or 
convulsions that do not result in hospitalisation. 
 
Development of drug dependency or drug abuse 
A Guide to interpreting the causality question 
When making an assessment of causality consider the following factors when deciding if there 
is a ‘reasonable possibility’ that an AE may have been caused by the drug. 

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• 
Time Course.  Exposure to suspect drug.  Has the patient actually received the suspect 
drug?  Did the AE occur in a reasonable temporal relationship to the administration of the 
suspect drug? 
• 
Consistency with known drug profile.  Was the AE consistent with the previous 
knowledge of the suspect drug (pharmacology and toxicology) or drugs of the same 
pharmacological class? Or could the AE be anticipated from its pharmacological 
properties? 
• 
De-challenge experience.  Did the AE resolve or improve on stopping or reducing the 
dose of the suspect drug? 
• 
No alternative cause.  The AE cannot be reasonably explained by another aetiology such 
as the underlying disease, other drugs, other host or environmental factors. 
• 
Re-challenge experience.  Did the AE reoccur if the suspected drug was reintroduced 
after having been stopped? AstraZeneca would not normally recommend or support a re-
challenge. 
• 
Laboratory tests.  A specific laboratory investigation (if performed) has confirmed the 
relationship. 
 
In difficult cases, other factors could be considered such as: 
• 
Is this a recognised feature of overdose of the drug? 
• 
Is there a known mechanism? 
 
Causality of ‘related’ is made if following a review of the relevant data, there is evidence for a 
‘reasonable possibility’ of a causal relationship for the individual case.  The expression 
‘reasonable possibility’ of a causal relationship is meant to convey, in general, that there are 
facts (evidence) or arguments to suggest a causal relationship. 
The causality assessment is performed based on the available data including enough 
information to make an informed judgment.  With limited or insufficient information in the 
case, it is likely that the event(s) will be assessed as ‘not related’. 
Causal relationship in cases where the disease under study has deteriorated due to lack of 
effect should be classified as no reasonable possibility.

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Appendix B International Airline Transportation Association (IATA) 6.2 
Guidance Document 
Labelling and shipment of biohazard samples 
International Airline Transportation Association (IATA) classifies biohazardous agents into 3 
categories.  For transport purposes the classification of infectious substances according to risk 
groups was removed from the Dangerous Goods Regulations (DGR) in the 46th edition 
(2005).  Infectious substances are now classified either as Category A, Category B or Exempt.  
There is no direct relationship between Risk Groups and categories A and B. 
Category A Infectious Substances are infectious substances in a form that, when exposure to 
it occurs, is capable of causing permanent disability, life-threatening or fatal disease in 
otherwise healthy humans or animals.  Category A pathogens are eg, Ebola, Lassa fever virus: 
• 
are to be packed and shipped in accordance with IATA Instruction 602. 
 
Category B Infectious Substances are infectious Substances that do not meet the criteria for 
inclusion in Category A.  Category B pathogens are eg, Hepatitis A, B, C, D, and E viruses, 
Human immunodeficiency virus (HIV) types 1 and 2.  They are assigned the following UN 
number and proper shipping name: 
• 
UN 3373 – Biological Substance, Category B. 
• 
are to be packed in accordance with UN3373 and IATA 650. 
 
Exempt - all other materials with minimal risk of containing pathogens 
• 
Clinical trial samples will fall into Category B or exempt under IATA regulations. 
• 
Clinical trial samples will routinely be packed and transported at ambient temperature in 
IATA 650 compliant packaging.  
• 
Biological samples transported in dry ice require additional dangerous goods specification 
for the dry-ice content. 
• 
IATA compliant courier and packaging materials should be used for packing and 
transportation and packing should be done by an IATA certified person, as applicable. 
• 
Samples routinely transported by road or rail are subject to local regulations which 
require that they are also packed and transported in a safe and appropriate way to contain 
any risk of infection or contamination by using approved couriers and packaging / 
containment materials at all times.  The IATA 650 biological sample containment 
standards are encouraged wherever possible when road or rail transport is used.

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Appendix C Genetic Research 
Rationale and objectives 
AstraZeneca intends to collect and store DNA for genetic research to explore how genetic 
variations may affect clinical parameters, risk and prognosis of diseases, and the response to 
medications.  Genetic research may lead to better understanding of diseases, better diagnosis 
of diseases or other improvements in health care and to the discovery of new diagnostics, 
treatments or medications.  
In addition, collection of DNA samples from populations with well described clinical 
characteristics may lead to improvements in the design and interpretation of clinical trials and, 
possibly, to genetically guided treatment strategies. 
Genetic research plan and procedures 
Selection of genetic research population 
Study selection record 
All subjects will be asked to participate in this genetic research.  Participation is voluntary and 
if a subject declines to participate there will be no penalty or loss of benefit.  The subject will 
not be excluded from any aspect of the main study. 
Inclusion criteria 
For inclusion in this genetic research, subjects must fulfil all of the inclusion criteria described 
in the main body of the Clinical Study Protocol and provide informed consent for the genetic 
sampling and analyses. 
Exclusion criteria 
Exclusion from this genetic research may be for any of the exclusion criteria specified in the 
main study or any of the following: 
• 
Previous allogeneic bone marrow transplant. 
• 
Non-leukocyte depleted blood products within 120 days of genetic sample collection. 
 
Discontinuation of subjects from this genetic research 
Specific reasons for discontinuing a subject from this genetic research are: 
Withdrawal of consent for genetic research:  Subjects may withdraw from this genetic 
research at any time, independent of any decision concerning participation in other aspects of 
the main study.  Voluntary discontinuation will not prejudice further treatment.  Procedures 
for discontinuation are outlined in Section 3.10 of the main Clinical Study Protocol. 

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Collection of samples for genetic research 
The blood sample for genetic research will be obtained from subjects on Day 1, Cycle 1.  
Although DNA is stable, early sample collection is preferred to avoid introducing bias through 
excluding subjects who may withdraw due to an adverse event (AE); such subjects would be 
important to include in any genetic analysis.  If for any reason the sample is not drawn on 
Day 1, Cycle 1, it may be taken at any visit until the last study visit.  Only one sample should 
be collected per subject for genetics during the study.  Samples will be collected, labelled, 
stored and shipped as detailed in the Laboratory Manual. 
Coding and storage of DNA samples 
The processes adopted for the coding and storage of samples for genetic analysis are 
important to maintain subject confidentiality.  Samples will be stored for a maximum of 
15 years from the date of last subject last visit, after which they will be destroyed.  DNA is a 
finite resource that is used up during analyses.  Samples will be stored and used until no 
further analyses are possible or the maximum storage time has been reached. 
An additional second code will be assigned to the blood ample either before or at the time of 
DNA extraction replacing the information on the sample tube.  Thereafter, the sample will be 
identifiable by the second, unique number only.  This number is used to identify the sample 
and corresponding data at the AstraZeneca genetics laboratories, or at the designated 
organisation. No personal details identifying the individual will be available to any person 
(AstraZeneca employee or designated organisations working with the DNA). 
The link between the subject enrolment/randomisation code and the second number will be 
maintained and stored in a secure environment, with restricted access at AstraZeneca or 
designated organisations.  The link will be used to identify the relevant DNA samples for 
analysis, facilitate correlation of genotypic results with clinical data, allow regulatory audit 
and to trace samples for destruction in the case of withdrawal of consent. 
Ethical and regulatory requirements 
The principles for ethical and regulatory requirements for the study, including this genetics 
research component, are outlined in Section 8 of the main Clinical Study Protocol. 
Informed consent 
The genetic component of this study is optional and the subject may participate in other 
components of the main study without participating in the genetic component.  To participate 
in the genetic component of the study the subject must sign and date both the consent form for 
the main study and the genetic component of the study.  Copies of both signed and dated 
consent forms must be given to the subject and the original filed at the study centre.  The 
Principal Investigator(s) is responsible for ensuring that consent is given freely and that the 

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subject understands that they may freely discontinue from the genetic aspect of the study at 
any time. 
Subject data protection 
AstraZeneca will not provide individual genotype results to subjects, any insurance company, 
any employer, their family members, general physician unless required to do so by law. 
Extra precautions are taken to preserve confidentiality and prevent genetic data being linked to 
the identity of the subject.  In exceptional circumstances, however, certain individuals might 
see both the genetic data and the personal identifiers of a subject.  For example, in the case of 
a medical emergency, an AstraZeneca Physician or an investigator might know a subject’s 
identity and also have access to his or her genetic data.  Also, Regulatory authorities may 
require access to the relevant files, though the subject’s medical information and the genetic 
files would remain physically separate. 
Data management 
Any genotype data generated in this study will be stored at a secure system at AstraZeneca 
and/or designated organisations to analyse the samples. 
The results from this genetic research may be reported in a separate report from the CSR or 
published in scientific journals.  
AstraZeneca and its designated organisations may share summary results (such as genetic 
differences from groups of individuals with a disease) from this genetic research with other 
researchers, such as Hospitals, Academic Organisation or Health Insurance Companies. This 
can be done by placing the results in scientific databases, where they can be combined with 
the results of similar studies to learn even more about health and disease. The researchers can 
only use this information for health-related research purposes. Researchers may see summary 
results but they will not be able to see individual subject data or any personal identifiers.  
Some or all of the clinical datasets from the main study may be merged with the genetic data 
in a suitable secure environment separate from the clinical database. 
Statistical methods and determination of sample size 
The number of subjects that will agree to participate in the genetic research is unknown.  It is 
therefore not possible to establish whether sufficient data will be collected to allow a formal 
statistical evaluation or whether only descriptive statistics will be generated.  A Statistical 
Analysis Plan will be prepared where appropriate. 

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Appendix D Acceptable Birth Control Methods 
Patients and their partners, who are sexually active and of childbearing potential, must agree 
to the use of highly effective forms of contraception [as listed below], throughout the period 
of study treatment or they must totally/truly abstain from any form of sexual intercourse (see 
below), when this is in line with their preferred and usual lifestyle.  Patients on savolitinib 
must continue contraception for at least 1 month (female patients) and 6 months (male 
patients) after their last dose.  
Acceptable Non-hormonal birth control methods include: 
• 
Total sexual abstinence (when this is in line with the preferred and usual lifestyle). 
Abstinence must continue for the total duration of study treatment and for at least 1 month 
after the last dose of savolitinib for females and for at least 6 months after the last dose of 
savolitinib for males. Periodic abstinence (eg, calendar ovulation, sympto-thermal post 
ovulation methods) and withdrawal are not acceptable methods of contraception. 
• 
Vasectomised sexual partner PLUS male condom. With participant assurance that partner 
received post-vasectomy confirmation of azoospermia. 
• 
Tubal occlusion PLUS male condom with spermicide. 
• 
Intra-uterine device (IUD) PLUS male condom with spermicide. Provided coils are 
copper-banded. 
• 
Acceptable hormonal methods: 
• 
Normal and low dose combined oral pills PLUS male condom with spermicide. 
• 
Etonogestrel implants (eg, Implanon, Norplan) PLUS male condom with spermicide. 
• 
Norelgestromin / Ethinyl Estradiol (EE) transdermal system PLUS male condom with 
spermicide. 
• 
Intravaginal device (eg, EE and etonogestrel) PLUS male condom with spermicide.  
• 
Cerazette (desogestrel) PLUS male condom with spermicide. Cerazette is currently the 
only highly efficacious progesterone based pill. 
• 
Intrauterine system [IUS] device (eg, levonorgestrel releasing IUS - Mirena®) PLUS male 
condom with spermicide. 
• 
Hormonal shot or injection (eg, Depo-Provera) PLUS male condom with spermicide.

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Appendix E Actions Required in Cases of Increases in Liver Biochemistry 
and Evaluation of Hy’s Law 
Introduction 
This Appendix describes the process to be followed in order to identify and appropriately 
report potential Hy’s Law (PHL) cases and Hy’s Law (HL) cases.  It is not intended to be a 
comprehensive guide to the management of elevated liver biochemistries.  Specific guidance 
on the management of liver abnormalities can be found in Section 6.8.1.2 of the protocol. 
During the course of the study the Investigator will remain vigilant for increases in liver 
biochemistry.  The investigator is responsible for determining whether a patient meets PHL 
criteria at any point during the study. 
All sources of laboratory data are appropriate for the determination of PHL and HL events.  
These include samples taken at scheduled study visits and other visits including central and all 
local laboratory evaluations, even if collected outside of the study visits.  For example, PHL 
criteria could be met by an elevated ALT from a central laboratory and/or elevated TBL from 
a local laboratory. 
The Investigator will also review adverse event (AE) data (for example, for AEs that may 
indicate elevations in liver biochemistry) for possible PHL events. 
The Investigator will participate, together with AstraZeneca clinical project representatives, in 
review and assessment of cases meeting PHL criteria to agree whether HL criteria are met.  
HL criteria are met if there is no alternative explanation for the elevations in liver 
biochemistry other than Drug Induced Liver Injury (DILI) caused by the Investigational 
Medicinal Product (IMP).  
The Investigator is responsible for recording data pertaining to PHL/HL cases and for 
reporting AEs and Serious Adverse Events (SAEs) according to the outcome of the review 
and assessment in line with standard safety reporting processes. 
Definitions 
Potential Hy’s Law (PHL) 
Aspartate Aminotransferase (AST) or Alanine Aminotransferase (ALT) ≥ 3x Upper Limit of 
Normal (ULN) together with Total Bilirubin (TBL) ≥ 2xULN at any point during the study 
following the start of study medication irrespective of an increase in Alkaline Phosphatase 
(ALP).  

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Hy’s Law (HL) 
AST or ALT ≥ 3xULN together with TBL ≥2xULN, where no other reason, other than the 
IMP, can be found to explain the combination of increases, eg, elevated ALP indicating 
cholestasis, viral hepatitis, another drug.   
For PHL and HL the elevation in transaminases must precede or be coincident with (ie, on the 
same day) the elevation in TBL, but there is no specified timeframe within which the 
elevations in transaminases and TBL must occur. 
Identification of potential Hy’s Law cases 
In order to identify cases of PHL it is important to perform a comprehensive review of 
laboratory data for any patient who meets any of the following identification criteria in 
isolation or in combination: 
• 
ALT ≥ 3xULN 
• 
AST ≥ 3xULN 
• 
TBL ≥ 2xULN 
 
The Investigator will without delay review each new laboratory report and if the identification 
criteria are met will: 
• 
Notify the AstraZeneca representative. 
• 
Determine whether the patient meets PHL criteria (see Definitions within this Appendix 
for definition) by reviewing laboratory reports from all previous visits. 
• 
Promptly enter the laboratory data into the laboratory eCRF. 
 
Follow-up: 
Potential Hy’s Law criteria not met 
If the patient does not meet PHL criteria the Investigator will: 
• 
Inform the AstraZeneca representative that the patient has not met PHL criteria. 
• 
Perform follow-up on subsequent laboratory results according to the guidance provided in 
the Clinical Study Protocol. 
 
Potential Hy’s Law criteria met 
If the patient does meet PHL criteria the Investigator will: 
• 
Notify the AstraZeneca representative who will then inform the central Study Team. 

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• 
Within 1 day of PHL criteria being met, the Investigator will report the case as an SAE of 
PHL; serious criteria 'Important medical event' and causality assessment 'yes/related' 
according to CSP process for SAE reporting. 
• 
For patients that met PHL criteria prior to starting IMP, the Investigator is not required to 
submit a PHL SAE unless there is a significant change* in the patient's condition. 
 
The AstraZeneca Study Physician contacts the Investigator, to provide guidance, discuss and 
agree an approach for the study patients’ follow-up (including any further laboratory testing) 
and the continuous review of data.  Subsequent to this contact the Investigator will: 
• 
Monitor the patient until liver biochemistry parameters and appropriate clinical symptoms 
and signs return to normal or baseline levels, or as long as medically indicated.  
• 
Complete the follow-up SAE form as required. 
• 
Investigate the aetiology of the event and perform diagnostic investigations as discussed 
with the AstraZeneca Study Physician.  
• 
Complete the three Liver eCRF Modules as information becomes available. 
 
Review and assessment of potential Hy’s Law cases 
The instructions in this Section should be followed for all cases where PHL criteria are met. 
As soon as possible after the biochemistry abnormality was initially detected, the AstraZeneca 
Study Physician contacts the Investigator in order to review available data and agree on 
whether there is an alternative explanation for meeting PHL criteria other than DILI caused by 
the IMP, to ensure timely analysis and reporting to health authorities within 15 calendar days 
from the date that the PHL criteria were met.  The AstraZeneca Global Clinical Lead (or 
equivalent) and Global Safety Physician will also be involved in this review together with 
other subject matter experts as appropriate.   
According to the outcome of the review and assessment, the Investigator will follow the 
instructions below. 
Where there is an agreed alternative explanation for the ALT or AST and TBL elevations, 
a determination of whether the alternative explanation is an AE will be made and 
subsequently whether the AE meets the criteria for a SAE: 
• 
If the alternative explanation is not an AE, record the alternative explanation on the 
appropriate eCRF. 
• 
If the alternative explanation is an AE/SAE, update the previously-submitted PHL SAE 
and AE eCRFs accordingly with the new information (reassessing event term, causality 
and seriousness criteria) following the AZ standard processes. 
 
If it is agreed that there is no explanation that would explain the ALT or AST and TBL 
elevations other than the IMP: 

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• 
Send updated SAE (report term ‘Hy’s Law’) according to AstraZeneca standard 
processes.  
− 
The ‘Medically Important’ serious criterion should be used if no other serious criteria 
apply. 
− 
As there is no alternative explanation for the HL case, a causality assessment of 
‘related’ should be assigned. 
 
If, there is an unavoidable delay, of over 15 calendar days in obtaining the information 
necessary to assess whether or not the case meets the criteria for HL, then it is assumed that 
there is no alternative explanation until such time as an informed decision can be made: 
• 
Provide any further update to the previously-submitted SAE of ‘Potential Hy’s Law’ 
(report term now ‘Hy’s Law case’) ensuring causality assessment is related to IMP and 
seriousness criteria is medically important, according to CSP process for SAE reporting. 
• 
Continue follow-up and review according to agreed plan.  Once the necessary 
supplementary information is obtained, repeat the review and assessment to determine 
whether HL criteria are still met.  Update the previously-submitted PHL SAE report 
following CSP process for SAE reporting, according to the outcome of the review and 
amending the reported term if an alternative explanation for the liver biochemistry 
elevations is determined. 
 
Actions Required for Repeat Episodes of Potential Hy’s Law 
This section is applicable when a patient meets PHL criteria on study treatment and has 
already met PHL criteria at a previous on study treatment visit. 
The requirement to conduct follow-up, review and assessment of a repeat occurrence(s) of 
PHL is based on the nature of the alternative cause identified for the previous occurrence.   
The investigator should determine the cause for the previous occurrence of PHL criteria being 
met and answer the following question: 
Was the alternative cause for the previous occurrence of PHL criteria being met found to be 
the disease under study eg, chronic or progressing malignant disease, severe infection or liver 
disease?   
If No: follow the process for reporting PHL as an SAE, described in “Potential Hy’s Law 
criteria met” of this Appendix. 
If Yes: 
Determine if there has been a significant change in the patient’s condition* compared with 
when PHL criteria were previously met: 

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• 
If there is no significant change no action is required. 
• 
If there is a significant change, follow the process for reporting PHL as an SAE, described 
in “Potential Hy’s Law criteria met” of this Appendix. 
 
* A ‘significant’ change in the patient’s condition refers to a clinically relevant change in any 
of the individual liver biochemistry parameters (ALT, AST or total bilirubin) in isolation or in 
combination, or a clinically relevant change in associated symptoms.  The determination of 
whether there has been a significant change will be at the discretion of the Investigator; this 
may be in consultation with the AstraZeneca Study Physician if there is any uncertainty. 
References 
FDA Guidance for Industry (issued July 2009) ‘Drug-induced liver injury: Premarketing 
clinical evaluation’: 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM174090.pdf  

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Appendix F Guidance for Evaluation of Objective Tumour Response 
Using RECIST 1.1 Criteria (Response Evaluation Criteria in 
Solid Tumours) 
F 1 
INTRODUCTION 
This appendix details the implementation of RECIST 1.1 Guidelines (Eisenhauer et al 2009) 
for the D5082C00003 study with regards to Investigator assessment of tumour burden 
including protocol-specific requirements for this study. 
F 2 
DEFINITION OF MEASURABLE, NON-MEASURABLE, 
TARGET AND NON-TARGET LESIONS 
Patients with at least one lesion (measurable and/or non-measurable) that can be accurately 
assessed at baseline by CT/MRI and is suitable for repeated assessment will be entered in this 
study.  
Measurable: 
A lesion, not previously irradiated, that can be accurately measured at baseline as ≥10 mm in 
the longest diameter (except lymph nodes which must have short axis ≥15 mm) with 
computed tomography (CT) or magnetic resonance imaging (MRI) and which is suitable for 
accurate repeated measurements. 
Non-measurable: 
1 
All other lesions, including small lesions (longest diameter <10 mm or pathological 
lymph nodes with ≥10 to <15 mm short axis at baseline*). 
2 
Truly non-measurable lesions include the following: bone lesions, leptomeningeal 
disease, ascites, pleural / pericardial effusion, inflammatory breast disease, lymphangitic 
involvement of skin or lung, abdominal masses/abdominal organomegaly identified by 
physical examination that is not measurable by CT or MRI. 
3 
Previously irradiated lesions.** 
4 
Skin lesions assessed by clinical examination. 
5 
Brain metastases. 
 
* Nodes with <10 mm short axis are considered non-pathological and should not be recorded 
or followed as NTL.   
**Localised post-radiation changes, which affect lesion sizes, may occur.  Therefore, lesions 
that have been previously irradiated will not be considered measurable and must be selected as 
Non-Target Lesions (NTL) at baseline and followed up as part of the NTL assessment. 

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Special Cases: 
Lytic bone lesions or mixed lytic–blastic lesions, with identifiable soft tissue components, can 
be considered measurable if the soft tissue component meets the definition of measurability.  
Blastic lesions are considered non-measurable. 
Cystic metastases can be considered measurable lesions if they meet the criteria for 
measurability from a radiological point of view, but if non-cystic lesions are present in the 
same patient; these should be selected as target lesions. 
Target lesions: 
A maximum of 5 measurable lesions (with a maximum of 2 lesions per organ), representative 
of all lesions involved suitable for accurate repeated measurement, should be identified as 
target lesions (TL) at baseline. 
Non-Target lesions: 
All other lesions (or sites of disease) not recorded as TL should be identified as NTL at 
baseline. 
F 3 
METHODS OF ASSESSMENT 
The same method of assessment and the same technique should be used to characterise each 
identified and recorded lesion at baseline and during follow-up visits. 
A summary of the methods to be used for RECIST assessment is provided below and those 
excluded from tumour assessments for this study are highlighted, with the rationale provided. 
Table F1  Summary of Methods of Assessment 
Target lesions 
Non-target lesions 
New lesions 
CT(preferred) 
CT (preferred) 
CT (preferred) 
MRI 
MRI 
MRI 
 
Clinical Examination 
Clinical Examination 
 
X-ray, Chest x-ray 
X-ray, Chest x-ray 
 
 
Ultrasound 
 
 
Bone scan 
 
 
FDG-PET 
 
F 3.1 
CT and MRI 
CT and MRI are generally considered to be the best currently available and reproducible 
methods to measure TL selected for response assessment and to assess NTL and identification 
of any new lesions. 

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In the D5082C00003 study it is recommended that CT examinations of the chest*, abdomen 
and pelvis will be used to assess tumour burden at baseline and follow-up visits.  CT 
examination with intravenous (i.v.) contrast media administration is the preferred method.  
MRI should be used where CT is not feasible or it is medically contra-indicated.  For brain 
lesion assessment, MRI is the preferred method. 
1 
*Chest, abdomen and pelvis CT/MRI scans should be performed at baseline. 
2 
*In those patients with thoracic lesions or upper abdomen lymphadenopathy identified at 
baseline assessment, chest, abdomen and pelvis should be performed at follow-up. 
3 
*In those patient with no disease present in the chest and no upper abdomen 
lymphadenopathy then follow-up is by abdomen and pelvis only. 
 
F 3.2 
Clinical examination 
Clinical examination will not be used for assessment of TL.  Clinically detected lesions can be 
selected as target lesions if they are assessed by CT or MRI scans.  Clinical examination can 
be used to assess NTL and to identify the presence of new lesions. 
F 3.3 
X-ray 
Chest X-ray 
Chest X-ray assessment will not be used for assessment of TL as they will be assessed by CT 
examination or MRI examination.  Chest X-ray can, however, be used to assess NTL and to 
identify the presence of new lesions. 
Plain X-ray 
Plain X-ray may be used as a method of assessment for bone NTL and to identify the presence 
of new bone lesions. 
F 3.4 
Ultrasound 
Ultrasound examination will not be used for assessment of TL and NTL as it is not a 
reproducible method, does not provide an accurate assessment of tumour size and it is 
subjective and operator dependent.  Ultrasound examination can, however, be used to identify 
the presence of new lesions.  If new clinical symptoms occur and an ultrasound is performed 
then new lesions should be confirmed by CT or MRI examination. 
F 3.5 
Endoscopy and laparoscopy 
Endoscopy and laparoscopy will not be used for tumour assessments, as they are not validated 
in the context of tumour assessment. 

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F 3.6 
Tumour markers 
Tumour markers will not be used. 
F 3.7 
Cytology and histology 
Histology will not be used as part of the tumour response assessment as per RECIST 1.1. 
Cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment is required when the measurable tumour has met criteria for response or 
stable disease.  In such circumstances, the cytology is necessary to differentiate between 
response / stable disease (an effusion may be a side effect of the treatment) and progressive 
disease (if the neoplastic origin of the fluid is confirmed).  Where cytology findings are not 
available, any effusion that significantly worsens (from trace to large) or appearance of 
clinically significant effusion (requiring change in drug therapy) during the study treatment 
will be considered to be progression of NTL, or disease progression due to new lesions. 
F 3.8 
Isotopic bone scan 
Bone lesions identified on an isotopic bone scan at baseline and confirmed by CT, MRI or 
X-ray at baseline should be recorded as NTL and followed by the same method as per baseline 
assessment. 
Isotopic bone scans may be used as a method of assessment to identify the presence of new 
bone lesions at follow-up visits.  New lesions will be recorded where a positive hot-spot that 
was not present on the baseline bone scan assessment is identified on a bone scan performed 
at any time during the study.  The Investigator should consider the positive hot-spot to be a 
significant new site of malignant disease and represent true disease progression in order to 
record the new lesion.  Confirmation by CT, MRI and x-ray is recommended where bone scan 
findings are equivocal. 
F 3.9 
FDG-PET scan 
FDG-PET scans may be used as a method for identifying new lesions, according with the 
following algorithm: New lesions will be recorded where there is positive FDG uptake* not 
present on baseline FDG-PET scan or in a location corresponding to a new lesion on CT/MRI 
at the same follow-up visit.  If there is no baseline FDG-PET scan available, and no evidence 
of new lesions on CT/MRI scans then follow-up CT/MRI assessments should be continued, 
scheduled as per protocol or clinical indicated, in order to confirm new lesions. 
* A positive FDG-PET scan lesion should be reported only when an uptake greater than twice 
that of the surrounding tissue is observed. 

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F 4 
TUMOUR RESPONSE EVALUATION 
F 4.1 
Schedule of evaluation 
Baseline assessments should encompass all areas of known predilection for metastases in the 
disease under evaluation and should additionally investigate areas that may be involved based 
on signs and symptoms of individual patients and should be performed no more than 28 days 
before randomisation, and ideally should be performed as close as possible to the start of 
study treatment.  Follow-up assessments will be performed every 6 weeks at the start of each 
cycle (±7 days), for the first year, then every 12 weeks (±1 week) relative to the date of 
randomisation, until objective disease progression as defined by RECIST 1.1.  See Table 1 
Study Schedule from Study Protocol for further information.  Any other sites at which new 
disease is suspected should also be adequately imaged at follow-up. 
If an unscheduled assessment was performed and the patient has not progressed, every attempt 
should be made to perform the subsequent assessments at their scheduled visits.  This 
schedule is to be followed in order to minimise any unintentional bias caused by some patients 
being assessed at a different frequency than other patients. 
F 4.2 
Target lesions (TL) 
F 4.2.1 
Documentation of target lesions 
A maximum of 5 measurable lesions, with a maximum of 2 lesions per organ (including 
lymph nodes), representative of all lesions involved should be identified as TL at baseline.  
Target lesions should be selected on the basis of their size (longest diameter for non-nodal 
lesions or short axis for nodal lesions), but in addition should be those that lend themselves to 
reproducible repeated measurements.  It may be the case that, on occasion, the largest lesion 
does not lend itself to reproducible measurement in which circumstance the next largest 
lesion, which can be measured reproducibly, should be selected.  The site and location of each 
TL should be documented as well as the longest diameter for non-nodal lesions (or short axis 
for lymph nodes).  All measurements should be recorded in millimetres.  At baseline the sum 
of the diameters for all TL will be calculated and reported as the baseline sum of diameters.  
At follow-up visits the sum of diameters for all TL will be calculated and reported as the 
follow-up sum of diameters. 
Special cases: 
1 
For TL measurable in 2 or 3 dimensions, always report the longest diameter.  For 
pathological lymph nodes measurable in 2 or 3 dimensions, always report the short axis.  
If the CT/MRI slice thickness used is >5mm, the minimum size of measurable disease at 
baseline should be twice the slice thickness of the baseline scan. 
2 
If a lesion has completely disappeared, the longest diameter should be recorded as 0 mm. 
3 
If a TL splits into two or more parts, then record the sum of the diameters of those parts. 

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4 
If two or more TL merge then the sum of the diameters of the combined lesion should be 
recorded for one of the lesions and 0 mm recorded for the other lesion(s). 
5 
If a TL is believed to be present and is faintly seen but too small to measure, a default 
value of 5 mm should be assigned.  If an accurate measure can be given, this should be 
recorded, even if it is below 5mm. 
6 
If a TL cannot be measured accurately due to it being too large, provide an estimate of the 
size of the lesion. 
7 
When a TL has had any intervention eg, radiotherapy, embolisation, surgery etc., during 
the study, the size of the TL should still be provided where possible. 
 
F 4.2.2 
Evaluation of target lesions 
This section provides the definitions of the criteria used to determine objective tumour visit 
response for TL. 
Table F2  Evaluation of target lesions 
Complete Response (CR) 
 
Disappearance of all target lesions since baseline.  Any   pathological 
lymph nodes selected as target lesions must have a reduction in short 
axis to <10 mm. 
Partial Response (PR) 
 
At least a 30% decrease in the sum of the diameters of TL, taking as 
reference the baseline sum of diameters 
Stable Disease (SD) 
 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD 
Progressive Disease (PD) 
 
At least a 20% increase in the sum of diameters of target lesions, taking 
as reference the smallest sum on study (this includes the baseline sum if 
that is the smallest on study).  In addition to the relative increase of 
20%, the sum must also demonstrate an absolute increase of at least 
5mm. 
Not Evaluable (NE) 
Only relevant if any of the target lesions were not assessed or not 
evaluable or had a lesion intervention at this visit.  Note: If the sum of 
diameters meets the progressive disease criteria, progressive disease 
overrides not evaluable as a target lesion response 
 
F 4.3 
Non-target lesions (NTL) 
F 4.3.1 
Evaluation of non-target lesions 
All other lesions (or sites of disease) not recorded as TL should be identified as NTL at 
baseline.  Measurements are not required for these lesions, but their status should be followed 
at subsequent visits.  At each visit an overall assessment of the NTL response should be 
recorded by the Investigator.  This section provides the definitions of the criteria used to 
determine and record overall response for NTL at the investigational site at each visit. 

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Table F3  Evaluation of non-target lesions 
Complete Response (CR) 
 
Disappearance of all non-target lesions since baseline.  All lymph nodes 
must be non-pathological in size (<10 mm short axis). 
 
Non-CR/Non PD 
 
Persistence of one or more NTL 
 
Progression (PD) 
 
Unequivocal progression of existing non-target lesions.  Unequivocal 
progression may be due to an important progression in one lesion only or in 
several lesions.  In all cases the progression MUST be clinically significant 
for the physician to consider changing (or stopping) therapy. 
 
Not Evaluable (NE) 
 
Only relevant when one or, some of the non-target lesions were not 
assessed and, in the Investigator's opinion, they are not able to provide an 
evaluable overall non-target lesion assessment at this visit. 
 
Note: For patients without target lesions at baseline, this is relevant if any of the non-target 
lesions were not assessed at this visit and the progression criteria have not been met. 
To achieve ‘unequivocal progression’ on the basis of non-target lesions, there must be overall 
level of substantial worsening in non-target disease such that, even in presence of SD or PR in 
target lesions, the overall tumour burden has increased sufficiently to merit discontinuation of 
therapy.  A modest ‘increase’ in the size of one or more non-target lesions is usually not 
sufficient to qualify for unequivocal progression status. 
F 4.4 
New lesions 
Details of any new lesions will also be recorded with the date of assessment.  The presence of 
one or more new lesions is assessed as progression. 
A lesion identified at a follow up assessment in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression. 
The finding of a new lesion should be unequivocal: ie, not attributable to differences in 
scanning technique, change in imaging modality or findings thought to represent something 
other than tumour. 
If a new lesion is equivocal, for example because of its small size, the treatment and tumour 
assessments should be continued until the new lesion has been confirmed.  If repeat scans 
confirm there is a new lesion, then the progression date should be declared using the date of 
the initial scan. 

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F 4.5 
Symptomatic deterioration 
Symptomatic deterioration is not a descriptor of an objective response: it is a reason for 
stopping study therapy.  Patients with ‘symptomatic deterioration’ requiring discontinuation of 
treatment without objective evidence of disease progression at that time should continue to 
undergo tumour assessments where possible until objective disease progression is observed. 
F 4.6 
Evaluation of Overall Visit Response 
The overall visit response will be derived using the algorithm shown in Table F4. 
Table F4  Overall Visit Response 
Target lesions 
Non-target lesions 
New lesions 
Overall response 
CR 
CR 
No 
CR 
CR 
NA 
No 
CR 
NA 
CR 
No 
CR 
CR 
Non CR / Non PD 
No 
PR 
CR 
NE 
No 
PR 
PR 
Non PD or NE 
No 
PR 
SD 
Non PD nor NE 
No 
SD 
NA 
Non CR / Non PD 
No 
SD (Non CR / Non PD) 
NE 
Non PD or NE 
No 
NE 
NA 
NE 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
CR = Complete Response, PR = Partial Response, SD = Stable Disease, PD = Progressive Disease, NE = 
not evaluable, NA = not applicable (only if relevant if there were no TL/NTL at baseline) 
F 5 
CENTRAL REVIEW 
The Contract Research Organisation (CRO) appointed by AstraZeneca to perform the 
independent central review for this study will provide specification for radiological imaging 
protocols in standard acquisition guidelines documentation. 
F 6 
REFERENCES 
Eisenhauer et al 2009 
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R.  New response 
evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1).  Eur J Cancer. 
2009;45:228-24

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Appendix G Performance Status (Karnofsky Scale) 
Table G1 Example of Performance Status (Karnofsky Scale) 
Description 
ECOG grade 
Karnofsky Scale 
Fully active, able to carry on 
all pre-disease performance 
without restriction. 
0 
100 
Normal, no complaints; no evidence of 
disease. 
90 
Able to carry on normal activity; minor 
signs or symptoms of disease. 
Restricted in physically 
strenuous activity, but 
ambulatory and able to carry 
out work of a light or 
sedentary nature, ie, light 
housework, office work. 
1 
80 
Normal activity with effort; some signs or 
symptoms of disease. 
70 
Cares for self but unable to carry on normal 
activity or to do work. 
Ambulatory and capable of 
self-care, but unable to carry 
out any work activities. Up and 
about more than 50% of 
waking hours. 
2 
60 
Requires occasional assistance but is able to 
care for most of personal needs. 
50 
Requires considerable assistance and 
frequent medical care. 
Capable of only limited self 
care, confined to bed or chair 
more than 50% of waking 
hours. 
3 
40 
Disabled; requires special care and 
assistance. 
30 
Severely disabled; hospitalisation is 
indicated although death not imminent. 
Completely disabled. Cannot 
carry on any self-care. Totally 
confined to bed or chair. 
4 
20 
Very ill; hospitalisation and active 
supportive care necessary. 
10 
Moribund. 

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Appendix H Guidance Regarding Potential Interactions of Savolitinib 
with Concomitant Medications 
There is currently no clinical data which suggests that there is a PK interaction between 
savolitinib and any concomitant medications. 
Based upon studies of in vitro liver microsomes and S9 fractions, savolitinib is metabolised by 
several metabolic enzymes, including both CYP450 enzymes and some NADPH-independent 
non-CYP enzymes.  
Concomitant use of drugs that are known to be CYP3A4 substrates of narrow therapeutic 
range or CYP3A4 sensitive substrates during the trial should be avoided as far as possible 
unless considered essential by the Investigator, in which case patients must be monitored 
closely for increased toxicity due to drug-drug interactions. 
These lists are not intended to be exhaustive, and similar restrictions will apply to other agents 
that are known to potently modulate CYP3A4 or CYP1A2 activity.  If required, please refer to 
full prescribing information for all drugs prior to co-administration with savolitinib. 
In vitro transporter data have predicted that there is a possibility that savolitinib and/or its 
major metabolite M2 inhibit the human efflux transporter breast cancer resistant protein 
(BCRP, ABCG2), and the hepatic uptake transporters organic anion transporting polypeptides 
1B1 and 1B3 (OATP1B1 and OATP1B3).  These findings plus data on cytochrome CYP3A4 
inhibition suggest an increased chance of a clinically relevant drug-drug interaction (DDI) 
between savolitinib and any co-administered drug that is a substrate for these transporters 
including statins.  There is the potential for several-fold over exposure of statins in patients 
taking standard doses of statins in addition to savolitinib.  Therefore, use of statins should be 
avoided as far as possible and, if considered necessary, the patients should be given the lowest 
available dose and closely monitored for the effects of increased statin exposure. 
In addition, savolitinib and M2 also inhibit multidrug and toxin extrusion proteins 1 (MATE1, 
SLC47A1) and 2K (MATE2K, SLC47A2) leading to an increased chance of a clinically 
relevant DDI between savolitinib and any co-administered drug that is a substrate for these 
transporters including metformin.  Thus, metformin should be used with caution in case of 
potential increased metformin exposure. 
For both savolitinib and sunitinib: Table H1 provides a list of potent inducers of CYP3A4.  
Tables H2 and H3 provides a list of potent inhibitors of CYP3A4 and CYP1A2. Table H4 
provides a list of CYP3A4 substrates which have a narrow therapeutic range and Table H5 
provides a list of CYP3A4 sensitive substrates.  Patients receiving or unable to discontinue 
potent inducers of CYP3A4 or potent inhibitors of CYP3A4 or CYP1A2 for 2 weeks before 

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the date of randomisation (3 weeks for St John’s Wort) are excluded from enrolment in the 
study. 
Table H1 
Drugs known to be strong inhibitors of CYP3A4 
Potent inhibitors of CYP3A4 enzymes  
boceprevir 
clarithromycin 
conivaptan 
cobicistat 
danoprevir 
elvitegravir/ RIT 
fluconazole 
grapefruit and grapefruit juicea 
indinavir 
itraconazole 
ketoconazole 
lopinavir/ritonavir 
LCL161 
mibefradil 
nefazodone 
nelfinavir 
posaconazole 
ritonavir 
saquinavir 
telaprevir 
telithromycin 
tipranavir/RIT 
troleandomycin 
voriconazole 
a 
Patients should abstain from eating grapefruit and Seville oranges (and other products containing these 
fruits eg, grapefruit juice or marmalade) during the study

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Table H2 
Drugs known to be strong inducers of CYP3A4 
Potent Inducers of CYP3A4 
avasimibe 
carbamazepine 
enzalutamide 
mitotane 
phenobarbital 
phenytoin 
rifabutin 
rifampin 
St. John's Wort 
 
Table H3 
Drugs known to be strong inhibitors of CYP1A2 
Potent inhibitors of CYP1A2 enzymes which may increase exposure to savolitinib  
fluvoxamine 
ciprofloxacin 
enoxacin 
 
Table H4 
Drugs known to be CYP3A4 substrates with a narrow therapeutic range 
CYP3A4 substrates know to have a narrow therapeutic range 
alfentanil 
cyclosporine 
diergotamine 
ergotamine 
fentanyl 
pimozide 
quinidine 
sirolimus 
tacrolimus 
 
 
 

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Table H5 
Drugs known to be CYP3A4 sensitive substrates 
CYP3A4 sensitive substrates 
alfentanil 
almorexant 
alpha-dihydroergocryptine 
aplaviroc 
aprepitant 
atazanavir 
atorvastatin 
avanafil 
BIRL 355 
bosutinib 
brecanavir 
brotizolam 
budesonide 
buspirone 
capravirine 
casopitant 
conivaptan 
danoprevir 
darifenacin 
darunavir 
dasatinib 
dronedarone  
ebastine  
eletriptan 
elvitegravir 
eplerenone 
everolimus 
felodipine 
ibrutinib 
indinavir 
ivacaftor 
L-771,688  
levomethadyl (LAAM) 
lomitapide 

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Table H5 
Drugs known to be CYP3A4 sensitive substrates 
CYP3A4 sensitive substrates 
lopinavir 
lovastatin  
lumefantrine 
lurasidone  
maraviroc 
midazolam 
midostaurin 
neratinib 
nisoldipine 
perospirone 
quetiapine 
ridaforolimus  
saquinavir 
sildenafil 
simeprevir 
simvastatin 
sirolimus 
tacrolimus 
terfenadine 
ticagrelor  
tilidine  
tipranavir 
tolvaptan 
triazolam  
vardenafil 
vicriviroc 
voclosporin 
 
Savolitinib is a weak competitive inhibitor of CYP2C8 (IC50=9.1μM).  Those drugs defined as 
potent 2C8 substrates (almost exclusively metabolised by 2C8, such as Repaglinide, 
Dasabuvir and Rosiglitazone) should be used with caution.  
Savolitinib is not a substrate of P-glycoprotein (Pgp) but is a weak inhibitor in vitro 
(IC50=17.9 uM).  Drugs that are known to be affected by Pgp such as digoxin, quinidine, 
loperamide, saquinavir and ritonavir should be used with caution. 

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Appendix I 
Guidance Regarding Potential Interactions of Savolitinib 
with Concomitant Medications Known to Prolong QT 
Interval 
Drugs that prolong QT interval 
The drugs listed in this section are taken from information provided by the Arizona Center for 
Education and Research on Therapeutics website (available at URL: 
https://www.crediblemeds.org). The website categorizes drugs based on the risk of inducing 
Torsades de Pointes (TdP). 
During screening the drugs that patients are currently prescribed should be checked opposite 
the ArizonaCert website above. 
Drugs with a known risk of Torsades de Pointes 
The following drugs prolong the QT interval and are clearly associated with a known risk of 
TdP, even when taken as recommended (Table I1). These drugs must have been discontinued 
prior to the start of administration of study treatment in accordance with guidance provided in 
the table below and should not be co-administered with savolitinib and for a period of one 
week after discontinuing study treatment. The list of drugs may not be exhaustive and is 
subject to change as new information becomes available. As such investigators are 
recommended to search the website to provide the most up to date information. 
Table I1 
Drugs with known risk of TdP 
Drugs with a known risk of TdP 
Drug name 
Withdrawal period prior to 
study treatment start 
Anagrelide, ciprofloxacin, clarithromycin, cocaine, droperidol, 
erythromycin, levofloxacin, ondansetron, papaverine hydrochloride, 
procainamide, sulpiride, sultopride, terfenadine, terlipressin 
2 days 
Cilostazol, cisapride, disopyramide, dofetilide, domperidone, flecainide, 
gatifloxacin, grepafloxacin, ibutilide, moxifloxacin, oxaliplatin, propofol, 
quinidine, roxithromycin, sevoflurane, sotalol, sparfloxacin, thioridazine 
7 days 
Azithromycin bepridil, citalopram, chlorpromazine, dronedarone, 
escitalopram, fluconazole, halofantrine, haloperidol, levomepromazine, 
levosulpiride, mesoridazine 
14 days 
Donepezil, terodiline 
3 weeks 
Levomethadyl, methadone, pimozide 
4 weeks 
Arsenic trioxide*, ibogaine 
6 weeks 
Pentamidine 
8 weeks 
Astemizole, probucol, vandetanib 
4 months 
Amiodarone, chloroquine 
1 year 
* Estimated value as pharmacokinetics of arsenic trioxide has not been studied 

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Appendix J 
Patient Reported Outcomes  
DISEASE RELATED SYMPTOM QUESTIONNAIRE 
Functional Assessment of Cancer Therapy Kidney Symptom Index-19 (FKSI-19) to be 
administered to patients in Stage 1 and Stage 2 
 
 

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HEALTH RELATED QUALITY OF LIFE QUESTIONNAIRE 
FACIT-F (Version 4) to be administered to patients in the Main Study. 
 

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HEALTH UTILITY QUESTIONNAIRE 
EuroQol Group. EQ-5D™ v.2 © 2009 is to be administered to patients in Stage 2.  
Under each heading, please tick the ONE box that best describes your health TODAY  
MOBILITY 
I have no problems in walking about   
 
 
 
 
 
 
I have slight problems in walking about  
 
 
 
 
 
 
I have moderate problems in walking about  
 
 
 
 
 
I have severe problems in walking about  
 
 
 
 
 
 
I am unable to walk about  
 
 
 
 
 
 
 
 
 
SELF-CARE 
I have no problems washing or dressing myself   
 
 
 
 
I have slight problems washing or dressing myself   
 
 
 
I have moderate problems washing or dressing myself  
 
 
 
I have severe problems washing or dressing myself   
 
 
 
I am unable to wash or dress myself  
 
 
 
 
 
 
 
USUAL ACTIVITIES (e.g. work, study, housework,  
family or leisure activities) 
I have no problems doing my usual activities  
 
 
 
 
 
I have slight problems doing my usual activities  
 
 
 
 
I have moderate problems doing my usual activities   
 
 
 
I have severe problems doing my usual activities  
 
 
 
 
I am unable to do my usual activities   
 
 
 
 
 
 

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PAIN / DISCOMFORT 
I have no pain or discomfort   
 
 
 
 
 
 
 
 
I have slight pain or discomfort  
 
 
 
 
 
 
 
 
I have moderate pain or discomfort  
 
 
 
 
 
 
 
I have severe pain or discomfort   
 
 
 
 
 
 
 
I have extreme pain or discomfort   
 
 
 
 
 
 
 
ANXIETY / DEPRESSION 
I am not anxious or depressed   
 
 
 
 
 
 
 
 
I am slightly anxious or depressed   
 
 
 
 
 
 
 
I am moderately anxious or depressed   
 
 
 
 
 
 
I am severely anxious or depressed  
 
 
 
 
 
 
 
I am extremely anxious or depressed   
 
 
 
 
 
 
 
 
 

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• 
We would like to know how good or bad your health is TODAY. 
• 
This scale is numbered from 0 to 100. 
• 
100 means the best health you can imagine. 
0 means the worst health you can imagine. 
• 
Mark an X on the scale to indicate how your health is TODAY.  
• 
Now, please write the number you marked on the scale in the box below.  
 
 
YOUR HEALTH TODAY  = 
 
 
 
 
 
 
 
 
 
10 
0 
20 
30 
40 
50 
60 
80 
70 
90 
100 
5 
15 
25 
35 
45 
55 
75 
65 
85 
95 
The best 
The worst 
health       
 you can 
imagine 

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NCI PRO-CTCAE™ ITEMS (Item Library Version 1.0) 
As individuals go through treatment for their cancer they sometimes experience different 
symptoms and side effects. For each question, please check or mark an 
 in the one box that 
best describes your experiences over the past 7 days… 
1. In the last 7 days, what was the SEVERITY of your DIFFICULTY SWALLOWING at its 
WORST? 
○ None 
○ Mild 
○ Moderate 
○ Severe 
○ Very severe 
 
2. In the last 7 days, what was the SEVERITY of your MOUTH OR THROAT SORES at 
their WORST? 
○ None 
○ Mild 
○ Moderate 
○ Severe 
○ Very severe 
In the last 7 days, how much did MOUTH OR THROAT SORES INTERFERE with your 
usual or daily activities? 
○ Not at all 
○ A little bit 
○ Somewhat 
○ Quite a bit 
○ Very much 
 
3. In the last 7 days, what was the SEVERITY of your DECREASED APPETITE at its 
WORST? 
○ None 
○ Mild 
○ Moderate 
○ Severe 
○ Very severe 
In the last 7 days, how much did DECREASED APPETITE INTERFERE with your usual 
or daily activities? 
○ Not at all 
○ A little bit 
○ Somewhat 
○ Quite a bit 
○ Very much 
 
4. In the last 7 days, how OFTEN did you have NAUSEA? 
○ Never 
○ Rarely 
○ Occasionally 
○ Frequently 
○ Almost constantly 
In the last 7 days, what was the SEVERITY of your NAUSEA at its WORST? 
○ None 
○ Mild 
○ Moderate 
○ Severe 
○ Very severe 
 
5. In the last 7 days, how OFTEN did you have VOMITING? 
○ Never 
○ Rarely 
○ Occasionally 
○ Frequently 
○ Almost 
constantly 
In the last 7 days, what was the SEVERITY of your VOMITING at its WORST? 

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○ None 
○ Mild 
○ Moderate 
○ Severe 
○ Very severe 
 
6. In the last 7 days, what was the SEVERITY of your CONSTIPATION at its WORST? 
○ None 
○ Mild 
○ Moderate 
○ Severe 
○ Very severe 
 
7. In the last 7 days, how OFTEN did you have LOOSE OR WATERY STOOLS 
(DIARRHEA)? 
○ Never 
○ Rarely 
○ Occasionally 
○ Frequently 
○ Almost 
constantly 
 
8. In the last 7 days, how OFTEN did you have PAIN IN THE ABDOMEN (BELLY 
AREA)? 
○ Never 
○ Rarely 
○ Occasionally 
○ Frequently 
○ Almost 
constantly 
In the last 7 days, what was the SEVERITY of your PAIN IN THE ABDOMEN (BELLY 
AREA) at its WORST? 
○ None 
○ Mild 
○ Moderate 
○ Severe 
○ Very severe 
In the last 7 days, how much did PAIN IN THE ABDOMEN (BELLY AREA) 
INTERFERE with your usual or daily activities? 
○ Not at all 
○ A little bit 
○ Somewhat 
○ Quite a bit 
○ Very much 
 
9. In the last 7 days, what was the SEVERITY of your SHORTNESS OF BREATH at its 
WORST? 
○ None 
○ Mild 
○ Moderate 
○ Severe 
○ Very severe 
In the last 7 days, how much did your SHORTNESS OF BREATH INTERFERE with 
your usual or daily activities? 
○ Not at all 
○ A little bit 
○ Somewhat 
○ Quite a bit 
○ Very much 
 
10. In the last 7 days, how OFTEN did you have ARM OR LEG SWELLING? 
○ Never 
○ Rarely 
○ Occasionally 
○ Frequently 
○ Almost 
constantly 
In the last 7 days, what was the SEVERITY of your ARM OR LEG SWELLING at its 
WORST? 

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○ None 
○ Mild 
○ Moderate 
○ Severe 
○ Very severe 
In the last 7 days, how much did ARM OR LEG SWELLING INTERFERE with your 
usual or daily activities? 
○ Not at all 
○ A little bit 
○ Somewhat 
○ Quite a bit 
○ Very much 
 
11. In the last 7 days, did you have any RASH? 
○ Yes 
○ No 
 
12. In the last 7 days, what was the SEVERITY of your HAND-FOOT SYNDROME (A 
RASH OF THE HANDS OR FEET THAT CAN CAUSE CRACKING, PEELING, 
REDNESS OR PAIN) at its WORST? 
○ None 
○ Mild 
○ Moderate 
○ Severe 
○ Very severe 
 
13. In the last 7 days, what was the SEVERITY of your DIZZINESS at its WORST? 
○ None 
○ Mild 
○ Moderate 
○ Severe 
○ Very severe 
In the last 7 days, how much did DIZZINESS INTERFERE with your usual or daily 
activities? 
○ Not at all 
○ A little bit 
○ Somewhat 
○ Quite a bit 
○ Very much 
 
14. In the last 7 days, how OFTEN did you have a HEADACHE? 
○ Never 
○ Rarely 
○ Occasionally 
○ Frequently 
○ Almost 
constantly 
In the last 7 days, what was the SEVERITY of your HEADACHE at its WORST? 
○ None 
○ Mild 
○ Moderate 
○ Severe 
○ Very severe 
In the last 7 days, how much did your HEADACHE INTERFERE with your usual or 
daily activities? 
○ Not at all 
○ A little bit 
○ Somewhat 
○ Quite a bit 
○ Very much 
 
15. In the last 7 days, what was the SEVERITY of your FATIGUE, TIREDNESS, OR 
LACK OF ENERGY at its WORST? 
○ None 
○ Mild 
○ Moderate 
○ Severe 
○ Very severe 

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In the last 7 days, how much did FATIGUE, TIREDNESS, OR LACK OF ENERGY 
INTERFERE with your usual or daily activities? 
○ Not at all 
○ A little bit 
○ Somewhat 
○ Quite a bit 
○ Very much 
 
16. In the last 7 days, did you BRUISE EASILY (BLACK AND BLUE MARKS)? 
○ Yes 
○ No 
Do you have any other symptoms that you wish to report? 
○ Yes  ○ No 
 
 
Please list any other symptoms: 
1. 
In the last 7 days, what was the SEVERITY of this symptom at its 
WORST? 
○ None 
○ Mild 
○ Moderate 
○ Severe 
○ Very severe 
2. 
In the last 7 days, what was the SEVERITY of this symptom at its 
WORST? 
○ None 
○ Mild 
○ Moderate 
○ Severe 
○ Very severe 
3. 
In the last 7 days, what was the SEVERITY of this symptom at its 
WORST? 
○ None 
○ Mild 
○ Moderate 
○ Severe 
○ Very severe 
4. 
In the last 7 days, what was the SEVERITY of this symptom at its 
WORST? 
○ None 
○ Mild 
○ Moderate 
○ Severe 
○ Very severe 
5. 
In the last 7 days, what was the SEVERITY of this symptom at its 
WORST? 
○ None 
○ Mild 
○ Moderate 
○ Severe 
○ Very severe 
 

Clinical Study Protocol 
AstraZeneca 
Savolitinib (AZD6094) 
19 December 2018 
D5082C00003 
 6.0 
CONFIDENTIAL AND PROPRIETARY 
157 of 157 
Appendix K Stages of Heart Failure – New York Heart Association 
Classification 
The Stages of Heart Failure – New York Heart Association Classification 
Class I (Mild) 
No Limitation of physical activity.  Ordinary physical activity does not cause undue fatigue, 
palpitation, or dyspnoea (shortness of breath). 
Class II (Mild) 
Slight limitation of physical activity.  Comfortable at rest, but ordinary physical activity 
results in fatigue, palpitation, or dyspnoea. 
Class III (Moderate) 
Marked limitation of physical activity.  Comfortable at rest, but less than ordinary physical 
activity results in fatigue, palpitation, or dyspnoea. 
Class IV (Severe) 
Unable to carry out any physical activity without discomfort.  Symptoms of cardiac 
insufficiency at rest. If any physical activity is undertaken, physical discomfort is increased. 
Reference 
The Criteria Committee of the New York Heart Association. Nomenclature and criteria for 
diagnosis of diseases of the heart and great vessels. 9th ed. Boston (MA): Little, Brown & Co; 
1994:253-256. 
 

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