Clinical trial NCT01599754
Conditions: Clear Cell Renal Carcinoma
Keywords: renal cell carcinoma axitinib tyrosine kinase inhibitor
Sponsor: SFJ Pharma Ltd. II
Start date: 2012-04-01; Completion date: 2018-05-01
Enrollment: 724 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this trial is to determine if adjuvant therapy with axitinib will prevent or delay the recurrence of renal cell cancer after surgery to remove the primary tumor in high risk patients.

Detailed description:
This is a prospective, randomized, double blind placebo controlled Phase 3 trial of oral axitinib starting at 5 mg twice daily given 3 years vs. placebo.

Approximately 700 patients will be randomized in a 1:1 ratio between axitinib vs placebo.

Arms: arm 1: None arm 2: None
Interventions: intervention 1: Axitinib intervention 2: Placebo
Intervention descriptions: intervention 1: Axitinib 5 mg twice daily intervention 2: Placebo twice daily

Protocol documents:
Prot_001.pdf: 
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CLINICAL PROTOCOL 
ADJUVANT AXITINIB TREATMENT OF RENAL CANCER: A RANDOMIZED 
DOUBLE-BLIND PHASE 3 STUDY OF ADJUVANT AXITINIB VS. PLACEBO IN 
SUBJECTS AT HIGH RISK OF RECURRENT RCC 
Compound: 
AG-013736 
Compound Name (if applicable): 
Axitinib 
Protocol Number: 
AP311736 
 
Phase: 
3 
Version and Date 
 
version - #10 March 21, 2017 
Good Clinical Practice Statement: 
 
 
 
 
 
 
This study is to be performed in full compliance with 
all International Conference on Harmonization (ICH) 
and all applicable local Good Clinical Practices 
(GCP) and regulations. All required study 
documentation will be archived per regulatory 
authorities’ requirements. 
 
This document contains confidential information belonging to Sponsor.  Except as otherwise 
agreed to in writing, by accepting or reviewing this document, you agree to hold this information in 
confidence and not copy or disclose it to others (except where required by applicable law) or use it 
for unauthorized purposes.  In the event of any actual or suspected breach of this obligation, 
Sponsor must be promptly notified. 


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SUMMARY 
Indication: 
Adjuvant treatment of patients at high risk of recurrent renal cell carcinoma (RCC) following 
nephrectomy. 
Background: 
Kidney cancer is diagnosed in approximately 270,000 people each year worldwide, and 
results in 120,000 deaths. RCC is the most common form of kidney cancer. Up to 30% of 
patients treated by nephrectomy for localized disease will relapse.  Hormonal, 
chemotherapeutic, and radiation therapy approaches have failed to significantly improve 
clinical outcomes, particularly for patients with metastatic disease. 
Approximately 45% of RCC patients present with “localized” disease (tumor, nodes, 
metastatis [TNM] Stage I/II) at the time of diagnosis, 25% “locally advanced” disease (Stage 
III) and 30% “metastatic” disease (TNM Stage IV).  Additionally, approximately 30% of 
patients with “localized” and “locally advanced” disease at the time of diagnosis will develop 
metastatic disease later on.  TNM Stage II, III and IV RCC patients have 5-year survival rates 
of 65-80%, 40-60% and 0-20%, respectively.  
Axitinib is an oral, potent and selective inhibitor of vascular endothelial growth factor 
(VEGF) receptors 1, 2, and 3. The safety and efficacy of axitinib is being evaluated in 
patients with a variety of solid tumors. 
VEGF receptors are critical components of the processes leading to the branching, extension, 
and survival of endothelial cells which form new blood vessels during angiogenesis, an 
absolute necessity for tumor growth beyond microscopic size. In nonclinical tumor mouse 
models, twice daily (BID) oral administration of axitinib demonstrated consistent and 
significant anti-tumor efficacy (marked inhibitory effect on local and distant tumor 
metastasis and prolonged animal survival). 
A Phase 2 study of single-agent axitinib in patients with cytokine-refractory metastatic RCC 
(mRCC) showed an objective response rate (ORR) of 44.2%, with 21 partial responders 
(PRs) and 2 complete responders (CRs) out of 52 patients.  The median time to progression 
(TTP) was 15.7 months and median overall survival (OS) was 29.9 months.  Another Phase 2 
study of single-agent axitinib in Japanese patients with cytokine-refractory mRCC 
demonstrated ORR of 50.0%, with 32 PRs out of 64 patients.  The median progression-free 
survival (PFS) was 11.0 months.  Both data were based on the assessment by an Independent 
Review Committee (IRC).  A third Phase 2 study of single-agent axitinib in patients with 
sorafenib-refractory mRCC showed ORR of 23% and a median PFS of 7.4 months (N=62).  
In a subset of 14 patients previously treated with both sorafenib and sunitinib, one patient 
achieved a PR and the median PFS was 7.1 months.  These results suggest that axitinib may 
provide clinical benefit to patients with mRCC following failure of prior systemic first-line 
therapy.   
In a Phase 3 study, efficacy and safety of axitinib versus (vs) sorafenib were confirmed in 
patients with advanced RCC following failure of one prior systemic first-line therapy.  


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Axitinib demonstrated a significantly longer PFS and higher ORR vs sorafenib with an 
acceptable safety profile as second-line therapy for mRCC.  Axitinib was approved by US 
Food and Drug Administration (FDA) in January 2012 with an indication for the treatment of 
advanced RCC after failure of one prior systemic therapy.  Axitinib was also approved in 
Japan, Korea and other countries in 2012 for the same indication. 
Objectives:  
Primary Objective: 
• To demonstrate an improvement in disease free survival (DFS) in patients at high risk 
of recurrent RCC randomly assigned to adjuvant axitinib (Arm A) vs. Placebo (Arm 
B) after nephrectomy. 
Secondary Objectives:  
• Compare OS associated with Arm A to that associated with Arm B 
• Assess safety/toxicity profile of administration of axitinib 
Trial Design: 
This is a prospective, randomized, double-blind placebo controlled Phase 3 trial of oral 
axitinib starting at 5 mg twice daily vs. placebo given for up to 3 years, with a minimum of 1 
year. The dose may be increased or decreased depending on individual patient tolerance of 
axitinib.   
A total of approximately 700 patients will be randomized in a 1:1 ratio between axitinib vs 
placebo.  Patients should begin study treatment within 7 days after randomization.  
Randomization will occur no sooner than 4 weeks post-nephrectomy and no later than 12 
weeks post-nephrectomy. 
Recurrence or occurrence of a secondary malignancy will be followed up, by clinic visit 
(See Section 6.4 for further details), until the time of the final analysis (regardless of the 
duration of treatment) every 16 weeks for the first 3 years from initiation of study treatment 
(also, at the end of treatment) and every 6 months thereafter for the remainder of the follow-
up period. 
All patients will be followed up for OS status (regardless of the duration of treatment) every 
16 weeks until the time for final DFS analysis.  Survival status can be ascertained by 
telephone contact.  At the time of final DFS analysis, OS results will be analyzed and 
summarized. 
Study Scheme: 
 
 
 
 
 
Arm A: axitinib 
Arm B: placebo 
Randomization 
Follow-up 
Treatment: Up to 3 years, with 
a minimum of 1 year 


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Endpoints: 
Primary Endpoint: 
• DFS is defined as the time interval from the date of randomization to the first date of 
recurrence (distant or local recurrence of RCC) or the occurrence of a secondary 
malignancy or death.  The primary DFS analysis will be based on assessments by the 
Independent Review Committee (IRC).  IRC will review all imaging data.  
Additionally, in cases for which there is site confirmation of recurrence or occurrence 
of a secondary malignancy in the absence of IRC imaging confirmation, available 
local histo-/cytopathology reports will also be reviewed by the IRC oncologist to 
determine confirmation of recurrence or occurrence of a secondary malignancy. 
• Recurrence refers to relapse of the primary tumor in situ or at metastatic sites.  The 
date of recurrence or the occurrence of a secondary malignancy is defined as the date 
of the tumor scan or the date of collection of the histo-/cytopathological specimen 
(for patients who have site confirmation of recurrence or occurrence of secondary 
malignancy in the absence of IRC imaging confirmation) that demonstrated 
unequivocal recurrence or a secondary malignancy according to protocol criteria.    If 
both imaging and histo-/cytopathological confirmation of recurrence or secondary 
malignancy are available, the earlier of the two dates will be considered. 
• For patients with no DFS event, DFS time will be censored at the date of the last scan 
prior to the time of the analyses.  Patients alive who do not have post-baseline disease 
assessments will have their DFS times censored at randomization.  For patients 
receiving further anti-tumor therapy prior to recurrence or occurrence of a secondary 
malignancy or death, DFS will be censored on the date of the last scan prior to taking 
the anti-tumor medication.  Patients who miss 2 or more consecutive tumor scans 
immediately followed by an event will be censored at the date of the last objective 
tumor assessment prior to the missing/not readable scans. 
Secondary Endpoints: 
• OS, defined as the time from the date of randomization to the date of death due to any 
cause.  In the absence of confirmation of death, survival time will be censored at the 
last date the patient is known to be alive.  Patients lacking data beyond randomization 
will have their survival times censored at randomization. 
• Type, incidence, severity (graded by the National Cancer Institute [NCI] Common 
Terminology Criteria for Adverse Events [CTCAE] Version 4.0), timing, seriousness, 
and relatedness of adverse events, and laboratory abnormalities. 
Trial Treatments: 
Patients will receive a starting dose of 5 mg of axitinib or placebo twice daily (BID) taken 
orally with or without food.  Study drug will be taken beginning on Day 1 of the study.  
Doses should be taken approximately 12 hours apart.  Patients should be instructed to take 
their doses at approximately the same times each day.  If a patient vomits or misses a dose, 
an additional dose should not be taken. The next prescribed dose should be taken at the usual 


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time.  Missed or vomited doses must be indicated in the source documents and Case Report 
Forms (CRFs).  Study drug will be administered in cycles of 4 weeks in duration. 
Patients who tolerate axitinib or placebo with no adverse events related to study drug above 
CTCAE Grade 2 for a consecutive 2 week period may have their dose increased by one dose 
level to a maximum of 10 mg BID (unless the patient’s blood pressure is >150/90 mm Hg or 
the patient is receiving antihypertensive medication).  The clinical judgment of the treating 
investigator should be exercised in titrating axitinib dose. 
Patients experiencing drug reaction should undergo dose modification as recommended in 
Section 5.3.4. 
Available Axitinib/Placebo Dose Levels: 
Dose Level 
Dose 
Dispensed As 
+2 
10 mg BID 
2 X 5 mg Tablets BID  
+1 
7 mg BID 
1 X 5 mg Tablet  BID + 2 X 1mg Tablets BID 
0 (Starting Dose) 
5 mg BID 
1 X 5 mg Tablet BID (twice daily) 
-1 
3 mg BID 
3 X 1 mg Tablets BID     
-2 
2 mg BID 
2 X 1 mg Tablets BID     
-3 
1 mg BID 
1 X 1 mg Tablet BID     
 
Statistical Methods: 
Two analysis populations will be defined: 
1. Intent-to-Treat Population: This population will include all patients who are 
randomized, with study drug assignment designated according to initial 
randomization, regardless of whether patients receive study drug or receive a different 
drug from that to which they were randomized.  This will be the primary population 
for evaluating all efficacy endpoints as well as patient characteristics;  
2. As-Treated Population: The as-treated population consists of all patients who 
received at least 1 dose of study drug with treatment assignments designated 
according to actual study drug received.  This population will be the primary 
population for evaluating study drug administration/compliance and safety.  
Sample Size Calculation:  
The patient population in this study can be classified into 4 risk groups based on American 
Joint Committee on Cancer (AJCC) TNM staging version 2010, Eastern Collaborative 
Oncology Group (ECOG) performance status (PS). Any Fuhrman grades are eligible. The 
patient risk groups will be as follows. Group a will be closed for further enrollment, to keep 
the number of patients of groups b, c, and d with about 90% or more: 
a. 
pT2, pN0 or pNx, M0 and ECOG PS 0-1 
b. pT3, pN0 or pNx, M0 and ECOG PS 0-1 
c. 
pT4, pN0 or pNx, M0 and ECOG PS 0-1 


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d. Any pT, pN1, M0 and ECOG PS 0-1 
Sample size was determined based on the analysis on the primary endpoint, DFS. 
The sample size for this study was calculated based on the following assumptions: 
• Time to DFS event follows an exponential distribution.  
• The percentage of patients randomized from the 4 risk groups, 2-year DFS rates for 
placebo arm and axitinib arm are assumed below: 
Categories 
Risk groups 
Percentage of 
patients 
2-year DFS rate for 
placebo arm 
2-year DFS rate for 
axitinib arm 
1 
a. pT2/pN0 or pNX/M0 
b. pT3/pN0 or pNX/M0 
90% 
70% 
79% 
2 
c. pT4/pN0 or pNX/M0 
1% 
35% 
61% 
3 
d. Any pT/pN1/M0 
9% 
33% 
51% 
 
The assumptions of 2-year DFS rates for the placebo arm and axitinib arm are equivalent to 
the assumptions of hazard ratios to be 0.66, 0.47, and 0.61 for the 3 categories 1, 2 and 3 
respectively.  Given the assumed distribution of patients randomized (1:1) into each of these 
categories, the overall hazard ratio is estimated to be 0.654. 
Based on the above assumptions, a minimal number of 245 DFS events will be required to 
provide 90% power to detect the statistical difference in DFS with HR ≤ 0.654 between the 
two treatment groups with 2-sided significance level of 0.05. 
Applying a 1:1 randomization and a planned accrual period of 24 months, a maximum study 
period of 60 months (5 years), and an assumed 23% drop-out rate by 18 months, it was 
estimated that approximately 700 patients will be enrolled.   
The final analysis will take place when approximately 245 DFS events are observed. 
Interim Analysis: 
A single interim analysis (IA) of efficacy and safety will be performed after approximately 
184 DFS events (approximately 75% of the total number of required events as assessed by 
the IRC) have occurred.  If the event occurrence pace is much slower than anticipated, the IA 
could be performed when less than 184 events observed (<75% of the total required) at 
sponsor’s discretion with the Data Monitoring Committee’s (DMC) consensus.  To protect 
the integrity of the study and to preserve the Type 1 error, a fraction of alpha will be spent at 
the interim analysis based on an O’Brien-Fleming stopping boundary.  
The objectives of the interim analysis will be: 
• To assess the safety, including any unexpected toxicity. 
• To allow for early stopping of the trial due to futility. 
• To assess the efficacy of the study drug to allow stopping of trial for success of 
efficacy. 


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Schedule of Assessments 
Screening 
Treatment with axitinib or placebo1 
Post-Treatment 
Protocol Activities and 
Forms to be Completed 
(See Protocol 
Section 6.1) 
Cycle 1 
(1 cycle = 4 weeks) 
Subsequent 
Cycles2 
EOT or 
Withdrawal3 
28 Days Post-  
Treatment 
DFS 
Follow-up 
Survival 
Follow-Up 
Day 1 
  
Day 15 
(-7/+2 days) 
Day 1 
 (-7/+2 days) 
 
(0/+7 days) 
 (-7/+7 days) 
 
Informed Consent4 
X 
 
 
 
 
 
 
 
Medical History, illnesses and 
demographics 
X 
 
 
 
 
 
 
 
Physical Examination 
X* 
X 
X5 
X 
X 
 
 
 
Vital signs6, body weight 
X* 
X 
X5 
X 
X 
 
 
 
Home Blood Pressure Monitoring7 
 
Throughout the study period 
 
 
 
 
Height 
X* 
 
 
 
 
 
 
 
Hematology8 
X* 
 
 
X 
X 
 
 
 
Blood Chemistry8 
X* 
 
 
X 
X 
 
 
 
Urinalysis8 
X* 
 
 
X 
X 
 
 
 
Thyroid Function Tests9 
 
X 
X5 
X 
X 
 
 
 
Pregnancy Test if applicable10 
X* 
 
 
 
 
 
 
 
12-lead electrocardiogram11 
X* 
 
 
 
 
 
 
 
ECOG Performance Status12 
X 
X 
 
X 
X 
 
 
 
CT or MRI of brain13 
X 
 
 
 
 
 
 
 
Tumor Imaging14 
X 
 
 
X 
Every 16 weeks 
X 
 
X 
 
Histo-/cytopathology15 
X 
X 
Study Randomization16 
X (Day -7 to 1) 
 
 
 
 
 
 
 
Study Treatment17 
 
X 
 
X 
 
 
 
 
Adverse Events18 
X 
X 
X5 
X 
X 
X 
 
 
Study Drug Compliance19 
 
 
 
X 
X 
 
 
 
Prior/Concomitant Medications 
and Treatments20 
X 
X 
X5 
X 
X 
X 
 
 
Follow-up Survival Status21 
 
 
 
 
 
 
 
X 
*: Should be assessed within 14 days of randomization. 
 
 
 
 
 
 
 
 


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Footnotes for Schedule of Assessments  
1. 
During Treatment:  Acceptable time windows for performing each assessment are described in the column headings.   
2. 
Subsequent Cycles: Assessments other than tumor imaging should be done at Day 1 of every cycle (4 weeks) until Cycle 5 Day1, then every 8 weeks thereafter starting from 
Cycle 7 Day 1. 
3. 
End of Treatment (EOT)/Withdrawal: At the end of the study or at withdrawal, these assessments should be performed if they were not performed within 7 days of the end 
of the study or at withdrawal. Tumor imaging should be obtained if they were not performed within 8 weeks of the end of the study or at withdrawal for patients who 
discontinue treatment for reasons other than disease progression. 
4. 
Informed Consent: Must be obtained before undergoing any study specific procedure and may occur prior to the screening period. 
5. 
Cycle 1 Day 15: Assessments should be performed via telephone contact or visit.  In case of telephone contact, only adverse events assessment should be performed. 
6. 
Vital signs: Temperature, blood pressure and pulse rate will be measured.  Blood pressure should be measured with the patient in the seated position after the patient has been 
sitting quietly for 5 minutes. 
7. 
Home Blood Pressure Monitoring: All patients will be provided a blood pressure monitoring device.  Patients should measure their blood pressure prior to taking each dose 
of study drug (twice daily) for the first 3 months, and once a week thereafter.  Following dose modification of study drug or anti-hypertensive medication, or changes of anti-
hypertensive medication, patients should restart blood pressure measurements prior to taking each dose of study drug for the first 3 months and once a week thereafter.  
Patients should record all blood pressure measurements in their patient diary.  Patients should be instructed by the study staff to contact their investigator immediately for 
guidance if their systolic blood pressure rises above 150 mm Hg, diastolic blood pressure rises above 100 mm Hg, or if they develop symptoms perceived to be related to 
elevated blood pressure (eg, headache, visual disturbance). 
8. 
Hematology, Blood Chemistry, Urinalysis: See Appendix 1 of the protocol for required tests.  Hematology, chemistry and urinalysis will be done 2 weeks prior to starting 
treatment (screening).  Results of the tests must be awaited before randomizing patients.  Thus, days for test results should be taken into consideration.  After the first cycle, 
the hematology, chemistry and urinalysis will be repeated at Day 1 of every cycle (4 weeks) until Cycle 5 Day1, then every 8 weeks thereafter starting from Cycle 7 Day 1.  If 
urine protein is ≥2+ by semi-quantitative method (ie, dipstick) at screening or on study, then urine protein:urine creatinine ratio should be performed.  PT/INR should be 
performed to monitor patients receiving concomitant warfarin or other anti-coagulants and when clinically indicated. 
9. 
Thyroid Function Tests: Thyroid Function Tests (TSH, free T3 and free T4) should be performed for all patients at baseline (Cycle 1 Day 1 pre-dose).  Subsequently, TSH 
should be done at Cycle 1 Day 15, Cycle 2 Day 1, Cycle 3 Day 1, Cycle 4 Day 1, Cycle 5 Day 1, then every 8 weeks thereafter starting from Cycle 7 Day 1.  TSH, Free T3 
and free T4 should be performed on the next visit for any patient who has elevated TSH.  Hypothyroidism should be treated per standard medical practice to maintain 
euthyroid state with a normal TSH. 
10. Pregnancy Testing: Patient of childbearing potential must have a negative pregnancy test within 14 days prior to the date of randomization and must be using appropriate 
birth control or practicing abstinence. Pregnancy tests may also be repeated as per request of IRB/IECs or if required by local regulations. 
11. 12-lead electrocardiogram (ECG):  To determine the QTc interval at screening, the average of three consecutive 12-lead ECGs should be done.  Screening ECG should be 
performed no more than 2 weeks prior to randomization. If the QTc interval is prolonged (>500 msec), the ECG should be re-read by a cardiologist at the site for 
confirmation.  ECGs should be repeated as clinically indicated. 
12. ECOG Performance Status (ECOG PS): Evaluation of ECOG PS at screening should reflect the patient condition just prior to nephrectomy.  Baseline ECOG PS should be 
made prior to randomization and start of treatment. Follow-up assessments will be done at Day 1 of every cycle (4 weeks) until Cycle 5 Day1, then every 8 weeks thereafter 
starting from Cycle 7 Day 1. 
13. CT or MRI of brain: To be done at screening and the images sent to the IRC for retrospective confirmation.  Patients with any evidence of brain metastasis must be 
excluded from the study.  Images should be submitted for IRC review before Week 8 post-nephrectomy to allow for return of the results before Week 12 and in the event a 
repeat scan is needed.  Brain CT or MRI within 12 weeks prior to randomization is acceptable regardless of whether it is before or after nephrectomy.  Subsequent CT or MRI 
of brain is not required, but may be performed if clinically indicated. 
14. Tumor Imaging: Pre-surgery images are requested, if available, and should be submitted for IRC review. Screening visit imaging will be reviewed by IRC, designated by the 
sponsor, and must be performed at least 3 weeks after nephrectomy.  Images should be submitted for IRC review before Week 8 post-nephrectomy to allow for return of the 
results before Week 12 and in the event a repeat scan is needed.  CT or MRI of the chest, abdomen and pelvis for DFS should be performed (regardless of the duration of 
treatment) every 16 weeks for the first 3 years from initiation of study treatment (also, at the end of treatment).  Allowable window for assessment is +/- 7 days.  Thereafter, 


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Footnotes for Schedule of Assessments  
imaging should be repeated every 6 months for the duration of the DFS follow-up period.  Additional imaging of potential disease sites should be performed whenever 
recurrence or occurrence of a secondary malignancy is suspected.  Bone scan (confirmatory imaging in addition to bone scan may be required), if clinically indicated. 
15. Histo-/cytopathology: Local histopathology confirmation of eligibility is required.  After randomization, in cases for which there is site confirmation of recurrence or 
occurrence of a secondary malignancy in the absence of IRC imaging confirmation, available local histo-/cytopathology reports should be submitted to the IRC for review. 
16. Study Randomization: Patients must be randomized by 12 weeks after nephrectomy.  Patient eligibility must be confirmed by IRC review for imaging and by a sponsor 
designated laboratory.  Patients must be randomized based on the assessment by the IRC when there is a discrepancy between the local and the IRC imaging review.  
17. Study Treatment: Should be started within 7 days after randomization.  It is not necessary to repeat the Day 1 procedures if treatment is not started on the same day as 
randomization.  Patients will receive either axitinib tablets at a starting dose of 5 mg BID or placebo according to randomization.  The axitinib/placebo dose may be adjusted 
up or down according to individual patient tolerance per protocol dose modification procedure.   Study drug are dispensed on Day 1 of each cycle. 
18. Adverse Events (AEs): Will be collected from the first day of study treatment until at least 28 days after the last on-study drug administration (Allowable window for 
assessment is 0/+7 days.), or until all serious or study drug-related toxicities have resolved or are determined to be “chronic” or “stable,” whichever is later.  Serious adverse 
events should be monitored and reported from the time that the patient provides informed consent and as described in the protocol.  
19. Study Drug Compliance: The study drug bottle(s) including any unused tablets will be returned to the clinic for drug accountability.   
20. Prior/Concomitant Medications and Treatments: Will be recorded from the time the patient has signed informed consent until 28 days after last treatment.  Allowable 
window for assessment is 0/+7 days.  Anti-tumor therapy should be recorded even after 28 days after last treatment. 
21. Follow-up Survival Status: Survival status information should be collected, approximately every 16 weeks (+/- 2 weeks) from DFS events, until the time for final DFS 
analysis.  Survival information can be done via telephone contact.   
 


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TABLE OF CONTENTS 
TABLE OF CONTENTS ................................................................................................................................... 10 
LIST OF TABLES .............................................................................................................................................. 12 
LIST OF FIGURES ............................................................................................................................................ 13 
LIST OF APPENDICES .................................................................................................................................... 13 
1. INTRODUCTION .......................................................................................................................................... 14 
1.1. Background ............................................................................................................................................... 14 
1.1.1. Renal Cell Carcinoma Epidemiology and Treatment ........................................................................ 14 
1.1.2. Molecular Formula ............................................................................................................................ 15 
1.1.3. Phase 2 Clinical Trials of Single-Agent Axitinib in mRCC.............................................................. 15 
1.1.3.1. Cytokine-Refractory mRCC Studies ......................................................................................... 15 
1.1.3.2. Sorafenib- and Sunitinib-Failure mRCC Study ......................................................................... 16 
1.1.4. Comparative Effectiveness Phase III Study of Axitinib in second line mRCC ................................ 16 
1.2. Rationale ................................................................................................................................................... 19 
2. TRIAL OBJECTIVES ................................................................................................................................... 19 
2.1. Primary Objective ..................................................................................................................................... 19 
2.2. Secondary Objectives ............................................................................................................................... 20 
3. TRIAL DESIGN ............................................................................................................................................. 20 
4. SUBJECT SELECTION ................................................................................................................................ 20 
4.1. Inclusion Criteria ...................................................................................................................................... 21 
4.2. Exclusion Criteria ..................................................................................................................................... 22 
4.3. Randomization Criteria ............................................................................................................................. 24 
4.4. Life Style Guidelines ................................................................................................................................ 25 
5. TRIAL TREATMENTS ................................................................................................................................ 25 
5.1. Allocation to Treatment ............................................................................................................................ 25 
5.2. Breaking the Blind .................................................................................................................................... 25 
5.3. Drug Supplies ........................................................................................................................................... 25 
5.3.1. Formulation and Packaging............................................................................................................... 26 
5.3.2. Preparation and Dispensing............................................................................................................... 26 
5.3.3. Administration .................................................................................................................................. 26 
5.3.4. Dose Interruption and Reduction ...................................................................................................... 27 
5.3.4.1. Management of Axitinib/Placebo-Related Adverse Events ...................................................... 27 
5.3.4.2. Axitinib/Placebo Dose Reduction for Hypertension ................................................................. 28 
5.3.4.3. Axitinib/Placebo Dose Reduction for Proteinuria ..................................................................... 29 
5.3.4.4. Axitinib/Placebo Dose Interruption for Surgery or Surgical Procedures .................................. 30 
5.3.5. Compliance ....................................................................................................................................... 30 
5.4. Drug Storage and Drug Accountability .................................................................................................... 30 
5.5. Prior/Concomitant Therapy ...................................................................................................................... 31 
5.5.1. Prior/Concomitant Medication .......................................................................................................... 31 


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5.5.2. Concomitant Radiotherapy................................................................................................................ 32 
6. TRIAL PROCEDURES ................................................................................................................................. 32 
6.1. Screening .................................................................................................................................................. 32 
6.1.1. Screening Procedures between Nephrectomy and Starting Treatment ............................................. 33 
6.1.2. Screening Procedures Within 2 Weeks Prior to Randomization ....................................................... 33 
6.2. Trial Period ............................................................................................................................................... 34 
6.2.1. Treatment Procedures First Cycle ..................................................................................................... 34 
6.2.1.1. Day 1 ......................................................................................................................................... 34 
6.2.1.2. Day 15 ....................................................................................................................................... 35 
6.2.2. Treatment Procedures Subsequent Cycles ........................................................................................ 35 
6.2.3. End of Study Treatment/Withdrawal from treatment Procedures ..................................................... 36 
6.3. 28 Days Post Treatment Follow-Up Visit ................................................................................................. 37 
6.4. Recurrence or occurrence of secondary malignancy and Survival Follow-Up ......................................... 37 
6.5. Patient Withdrawal ................................................................................................................................... 38 
6.5.1. Withdrawal from treatment ............................................................................................................... 38 
6.5.2. Withdrawal from trial........................................................................................................................ 38 
7. ASSESSMENTS ............................................................................................................................................. 39 
7.1. Efficacy Assessments ............................................................................................................................... 39 
7.1.1. Primary Endpoint .............................................................................................................................. 40 
7.1.2. Secondary Endpoints......................................................................................................................... 41 
7.2. Safety Assessments ................................................................................................................................... 41 
7.2.1. Adverse Events ................................................................................................................................. 41 
7.2.2. Laboratory Safety Assessments ........................................................................................................ 41 
7.2.3. Other Safety Assessments ................................................................................................................. 42 
8. Adverse Event Reporting ............................................................................................................................... 42 
8.1. Adverse Events ......................................................................................................................................... 42 
8.2. Reporting Period ....................................................................................................................................... 43 
8.3. Definition of an Adverse Event ................................................................................................................ 43 
8.4. Abnormal Test Findings ........................................................................................................................... 44 
8.5. Serious Adverse Events ............................................................................................................................ 44 
8.6. Hospitalization .......................................................................................................................................... 45 
8.7. Severity Assessment ................................................................................................................................. 46 
8.8. Causality Assessment ............................................................................................................................... 47 
8.9. Exposure In Utero ..................................................................................................................................... 47 
8.10. Withdrawal Due to Adverse Events (See Also Patient Withdrawal) ...................................................... 48 
8.11. Eliciting Adverse Event Information ...................................................................................................... 48 
8.12. Reporting Requirements ......................................................................................................................... 48 
8.12.1. Serious Adverse Event Reporting Requirements ............................................................................ 49 
8.12.2. Non-Serious Adverse Event Reporting Requirements .................................................................... 49 
9. DATA ANALYSIS/STATISTICAL METHODS ........................................................................................ 49 
9.1. Sample Size Determination ...................................................................................................................... 50 


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9.2. Efficacy Analysis ...................................................................................................................................... 51 
9.2.1. Analysis of Primary Endpoint ........................................................................................................... 51 
9.2.2. Analysis of Secondary Endpoints ..................................................................................................... 52 
9.3. Analysis of Other Endpoints ..................................................................................................................... 52 
9.3.1. Patient Disposition ............................................................................................................................ 52 
9.3.2. Baseline Characteristics .................................................................................................................... 52 
9.3.3. Study drug Administration/Compliance............................................................................................ 52 
9.4. Safety Analysis ......................................................................................................................................... 52 
9.4.1. Analysis of Adverse Events .............................................................................................................. 52 
9.4.2. Analysis of Clinical Laboratory Data................................................................................................ 53 
9.4.3. Prior/Concomitant Medications and Non Drug Treatments/Procedures ........................................... 53 
9.4.4. Vital Sign and ECOG PS .................................................................................................................. 53 
9.5. Interim Analysis........................................................................................................................................ 53 
9.6. Data Monitoring Committee ..................................................................................................................... 54 
9.7. Independent Review Committee (IRC) .................................................................................................... 55 
10. QUALITY CONTROL AND QUALITY ASSURANCE .......................................................................... 55 
11. DATA HANDLING AND RECORD KEEPING ....................................................................................... 55 
11.1. Case Report Forms/Electronic Data Record ........................................................................................... 55 
11.2. Record Retention .................................................................................................................................... 56 
12. ETHICS ......................................................................................................................................................... 56 
12.1. Institutional Review Board (IRB)/Independent Ethics Committee (IEC) ............................................... 56 
12.2. Ethical Conduct of the Trial .................................................................................................................... 56 
12.3. Patient Information and Consent ............................................................................................................ 56 
13. DEFINITION OF END OF TRIAL ............................................................................................................ 57 
14. SPONSOR DISCONTINUATION CRITERIA ......................................................................................... 57 
15. PUBLICATION OF TRIAL RESULTS ..................................................................................................... 57 
16. REFERENCES ............................................................................................................................................. 58 
 
LIST OF TABLES 
Table 1 
Adverse Reaction (Phase III study) ............................................................................18 
Table 2 
Available Axitinib/Placebo Dose Levels ....................................................................27 
Table 3 
Criteria for Dose Modification for Axitinib/Placebo – Related Adverse 
Events Other Than Hypertension Or Proteinuria ........................................................27 
Table 4 
 Hypertension Management Plan for Axitinib/Placebo ..............................................29 
 


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LIST OF FIGURES 
Figure 1 Molecular Formula .......................................................................................................15 
Figure 2 Kaplan-Meier Curve for Progression- Free Survival by Independent 
Assessment for the Overall Population .......................................................................17 
Figure 3 Screening Procedures ...................................................................................................33 
 
LIST OF APPENDICES 
Appendix 1. Required Laboratory Tests ........................................................................................62 
Appendix 2. ECOG Performance Status ........................................................................................63 
Appendix 3. National Cancer Institute (NCI) Common Terminology Criteria for 
Adverse Events (CTCAE) ..........................................................................................64 
Appendix 4. Nephrectomy Procedure. ...........................................................................................65 
Appendix 5. Abbreviations and Definitions of Terms ...................................................................66 
 


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1. INTRODUCTION 
1.1. Background 
1.1.1. Renal Cell Carcinoma Epidemiology and Treatment 
Kidney cancer is diagnosed in approximately 270,000 people each year worldwide, and 
results in 120,000 deaths. Renal cell carcinoma (RCC) is the most common form of kidney 
cancer.1  Up to 30% of patients treated by nephrectomy for localized disease will relapse.2  
Hormonal, chemotherapeutic, and radiation therapy approaches have failed to significantly 
improve clinical outcomes, particularly for patients with metastatic disease. 
Clear cell RCC, which represents 75% to 85% of the RCC population, frequently displays 
allelic loss on chromosome 3p, accompanied by mutational inactivation of the Von 
Hippel-Lindau (VHL) tumor suppressor gene.3, 4  VHL-associated RCC are known for their 
vascularity and these tumors produce high levels of vascular endothelial growth factor 
(VEGF). 5, 6, 7  In addition, recent studies suggest that in sporadic clear cell RCC, increased 
expression of VEGF is closely correlated with neovascularization, which is a prerequisite of 
tumor growth and metastasis.8  RCC tumors overexpress the receptors for these peptides.  
These ligands and receptors may be involved in the autocrine stimulation of tumor cell 
growth, or in the paracrine stimulation of neovascular or stromal fibroblast growth that 
supports tumor expansion. 
Approximately 45% of RCC patients present with “localized” disease (tumor, nodes, 
metastatis [TNM] Stage I/II) at the time of diagnosis, 25% “locally advanced” disease (Stage 
III) and 30% “metastatic” disease (TNM Stage IV).  Additionally, approximately 30% of 
patients with “localized” and “locally advanced” disease at the time of diagnosis will develop 
metastatic disease later on.  TNM Stage II, III and IV RCC patients have 5 year survival rates 
of 65-80%, 40-60% and 0-20%, respectively.  
Hormonal, chemotherapeutic, and radiation therapy approaches have failed to significantly 
improve clinical outcomes for patients with metastatic RCC (mRCC).  Recently-published 
trials included reports on thalidomide, 5-FU, and cis-retinoic acid, none of which showed 
clear benefit.  Studies of chemotherapy combined with cytokine therapy have also been 
discouraging.  Notwithstanding, cytokine therapies have been commonly used in the 
treatment of mRCC albeit with limited anti-tumor response.  Interferon-α (IFN-α) has an 
approximately 15% objective response rate (ORR) in appropriately selected individuals.10  In 
general, these patients have non-bulky pulmonary and/or soft tissue metastases with excellent 
PS (Eastern Collaborative Oncology Group (ECOG) performance status (PS) 0 or 1) without 
weight loss.  These responses are rarely complete or durable, but the result of a study 
suggests that IFN-α improves survival.11  Administration of high-dose interleukin-2 (IL-2) 
appears to have a similar overall response rate to IFN-α, but with approximately 5% of the 
appropriately selected patients having durable complete remissions.  Combinations of IL-2 
and IFN-α have been studied, but have not shown an overall survival (OS) advantage over 
monotherapy.  The optimum dose of IL-2 is unknown.  High-dose therapy has been approved 
in the United States, and while it appears to be associated with higher response rates, the 
incidence of toxic effects is also high.12, 13, 14, 15  Low-dose IL-2 regimens produce lower 


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response rates but can be administered with fewer toxic effects, especially hypotension.16  
Attempts to improve relapse-free survival and OS using cytokine or immune-based 
treatments were equally discouraging providing no evidence for improved relapse-free or 
OS.17, 18, 19 
Several anti-angiogenic agents have shown activity in the treatment of mRCC.  In the 
first-line treatment of mRCC, sunitinib has demonstrated dramatically improved median 
progression free survival (PFS) over IFN (11 months vs 5 months; hazard ratio 0.42; p < 
0.001)20 and is now considered to be the standard of care for the first-line treatment of 
patients with mRCC.  In similar first-line setting, the final analysis of a randomized Phase 3 
(AVOREN) trial of bevacizumab in combination with IFN versus IFN alone demonstrated 
that bevacizumab significantly improved PFS and showed a trend toward improvement in OS 
in patients with mRCC. 21, 22  In second-line setting after cytokine failure, sorafenib has 
demonstrated superior PFS over placebo with the median PFS of 5.5 months.23    
1.1.2. Molecular Formula  
Axitinib, a substituted indazole derivative, is an oral, potent, and selective inhibitor of VEGF 
receptors 1, 2, 3.  The molecular formula is C22H18N4OS with molecular weight of 386.47.  
The chemical name is 
N-Methyl-2-[3-((E)-2-pyridin-2-yl-vinyl)-1H-indazol-6-ylsulfanyl]-benzamide:  
Figure 1 Molecular Formula 
H
N
N
S
C O N H Me
N
 
 
1.1.3. Phase 2 Clinical Trials of Single-Agent Axitinib in mRCC 
Three Phase 2 studies have been conducted to explore the safety and efficacy of axitinib in 
mRCC patients. 
1.1.3.1. Cytokine-Refractory mRCC Studies 
The Phase 2 study (Protocol A4061012) enrolled 52 patients with mRCC who were 
refractory to cytokine treatment.  Two complete responses (CRs) and 21 partial responders 


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(PRs) were observed, for an ORR of 44.2%.  The median time to progression (TTP) was 15.7 
months and the median OS was 29.9 months. 24 
Long-term survival data were collected via an observational study (Protocol A4061065). 25 
Of the 52 patients, 35 died of progressive disease, 5 died of “unknown causes,” 10 were 
alive, and 2 were lost to follow-up. Median follow-up for OS was 5.9 yrs. The 5-year 
survival rate was 20.6% (95% confidence interval [CI], 10.9–32.4%). Treatment-emergent, 
all-causality grade ≥3 adverse events for the 52 patients included diarrhea (19%), fatigue 
(19%), hypertension (17%), weight loss (8%), and dehydration, myocardial infarction, and 
stomatitis (6% each). Hypothyroidism (all grades) was observed in 23%. Comparing the 
characteristics of the 5-year survivors (n = 10) vs <5-year survivors (n = 40), the former had 
higher ORR (100% vs 30%), longer axitinib therapy duration (median 5.8 years vs 0.67 
years), and better baseline PS (80% vs 53% with PS 0) but were of similar median age (57 vs 
60), gender (80% vs 75% males), and risk factors (50% vs 40% with zero MSKCC factors). 
Subsequently, the Phase 2 Study (Protocol A4061035) in Japanese patients with advanced 
RCC who were refractory to first line cytokine containing regimen was conducted. 26  64 
patients were enrolled in this study.  Based on the results from IRC, confirmed partial 
response was observed in 32 patients, and ORR was 50.0%.  In addition, median PFS was 11 
months as of data cutoff date (February 26, 2010). 
1.1.3.2. Sorafenib- and Sunitinib-Failure mRCC Study 
The third Phase 2 study (Protocol A4061023) enrolled 62 patients with mRCC who were 
refractory to sorafenib treatment. In addition to prior sorafenib, most of the patients received 
prior sunitinib and (or) other drugs before enrollment in this study. The analysis of all 62 
evaluable patients indicates 14 PRs (23%) and a median PFS of 7.4 months.  The median 
PFS for the 14 patients who failed both sunitinib and sorafenib was 7.1 months.27 
1.1.4. Comparative Effectiveness Phase III Study of Axitinib in second line mRCC 
The primary objective of this pivotal Phase 3 (AXIS) study was to compare the PFS of 
patients with mRCC receiving axitinib vs another TKI, sorafenib, following failure of 1 prior 
systemic first-line regimen.28  The secondary objectives were to compare the OS and ORR of 
patients in each arm, evaluate the safety and tolerability of axitinib, estimate the duration of 
response (DR) of patients in each arm, and compare the FACT-Advanced Kidney Cancer 
Symptom Index (FKSI) and EuroQoL-5D (EQ-5D). 
Between 15 September 2008 and 23 July 2010, a total of 723 patients with mRCC were 
randomized into this Phase 3 study, treated with either axitinib or sorafenib, and were 
followed for safety and efficacy. Enrolled patients were ≥18 years old, had histologically 
confirmed mRCC, had an ECOG PS of 0 or 1, and had failed 1 prior systemic, first-line 
regimen, which must have contained 1 or more of the following: sunitinib, bevacizumab + 
IFN-α, temsirolimus, or cytokine(s). Demographic and baseline characteristics were well 
balanced between both treatment arms. 
The study enrolled 361 patients in the axitinib arm and 362 in the sorafenib arm. Based on 
the  blinded IRC review of the overall analysis, the median PFS was 6.7 months (95% CI 


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[6.3, 8.6]) in the axitinib arm and 4.7 months (95% CI [4.6, 5.6]) in the sorafenib arm, with a 
hazard ratio of 0.665 (95% CI [0.544, 0.812]) and p-value of <0.0001 (1-sided).  
In the subgroup of 251 patients who received prior treatment with cytokines (126 in the 
axitinib arm and 125 in the sorafenib arm), the median PFS in the axitinib arm was 12.1 
months (95% CI [10.1, 13.9]) compared with 6.5 months (95% CI [6.3, 8.3]) in the sorafenib 
arm, with a hazard ratio of 0.464 (95% CI [0.318, 0.676]) and a p-value of <0.0001 (1-sided). 
The sorafenib control arm replicated prior Phase 3 sorafenib data (median PFS of 5.5 
months) in a cytokine-refractory population.  In the subgroup of 389 patients who had 
received prior treatment with sunitinib-containing regimen (194 in the axitinib arm and 195 
in the sorafenib arm), the median PFS in the axitinib arm was 4.8 months (95% CI [4.5, 6.4]) 
compared with 3.4 months (95% CI [2.8, 4.7]) in the sorafenib arm, with a hazard ratio of 
0.741 (95% CI [0.573, 0.958]) and a p-value of 0.0107 (1-sided). The study enrolled only 59 
patients who received prior treatment with bevacizumab-containing regimen (29 in the 
axitinib arm and 30 in the sorafenib arm) and 24 patients who received prior treatment with 
temsirolimus-containing regimen (12 in the axitinib arm and 12 in the sorafenib arm). Due to 
small numbers of patients in these subgroups, no firm conclusions can be made.  
Figure 2 Kaplan-Meier Curve for Progression-Free Survival by Independent 
Assessment for the Overall Population 
 
 
Since only a total of 223 patients (approximately 30%) had died as of the data cutoff date (31 
August 2010), the data for OS are not mature and likely to change with further followup.  As 
of the data cutoff date, the median OS was not reached in the axitinib arm and was 18.9 
months in the sorafenib arm, with a hazard ratio of 1.008 with a 95% CI of (0.774, 1.313) 
and a 1-sided p-value of 0.525. Further follow-up of OS is continuing.  
Table 1 presents adverse reactions reported in patients who received axitinib or sorafenib:  
Axitinib 


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Table 1 
Adverse Reaction (Phase III study) 
Adverse Reaction a 
Axitinib 
Sorafenib 
N=359 
N=355 
All Grades 
b 
Grade 3/4 
All Grades 
b 
Grade 3/4 
% 
% 
% 
% 
Diarrhea  
55  
11  
53  
7  
Hypertension  
40  
16  
29  
11  
Fatigue  
39  
11  
32  
5  
Decreased appetite 
34  
5  
29  
4  
Nausea  
32  
3  
22  
1  
Dysphonia  
31  
0  
14  
0  
Palmar-plantar erythrodysesthesia syndrome  
27  
5  
51  
16  
Weight decreased  
25  
2  
21  
1  
Vomiting  
24  
3  
17  
1  
Asthenia  
21  
5  
14  
3  
Constipation  
20  
1  
20  
1  
Hypothyroidism  
19  
<1  
8  
0  
Cough  
15  
1  
17  
1  
Mucosal inflammation  
15  
1  
12  
1  
Arthralgia  
15  
2  
11  
1  
Stomatitis  
15  
1  
12  
<1  
Dyspnea  
15  
3  
12  
3  
Abdominal pain  
14  
2  
11  
1  
Headache  
14  
1  
11  
0  
Pain in extremity  
13  
1  
14  
1  
Rash  
13  
<1  
32  
4  
Proteinuria  
11  
3  
7  
2  
Dysgeusia  
11  
0  
8  
0  
Dry skin  
10  
0  
11  
0  
Dyspepsia  
10  
0  
2  
0  
Pruritus  
7  
0  
12  
0  
Alopecia  
4  
0  
32  
0  
Erythema  
2  
0  
10  
<1  
a
Percentages are treatment-emergent, all-causality events  
b 
National Cancer Institute Common Terminology Criteria for Adverse Events, Version 3.0 
 


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1.2. Rationale 
The axitinib response rate in cytokine-refractory patients is higher than reported response 
rates with cytokines or chemotherapeutics in the second-line setting.  Additionally, axitinib 
response rates in the second-line setting are better than response rates reported in the 
first-line setting with cytokines or chemotherapeutics alone or in combination.  The 5-year 
survival rate was 20.6% (95% CI, 10.9–32.4%) in patients with mRCC who were refractory 
to cytokine treatment.  Axitinib demonstrated a significantly longer PFS and higher ORR vs 
sorafenib with an acceptable safety profile as second-line therapy for mRCC.  Axitinib was 
approved by US Food and Drug Administration (FDA) in January 2012 with an indication 
for the treatment of advanced RCC after failure of one prior systemic therapy.  Axitinib was 
also approved in Japan, Korea and other countries in 2012 for the same indication.  The 
efficacy and safety of axitinib in patients with mRCC support further clinical study to pursue 
clinical benefits of adjuvant axitinib treatment for patients at high risk of recurrent RCC after 
nephrectomy. 
Risk stratification has become increasingly important in the management of patients newly 
diagnosed with RCC.  Tumor stage is currently the principal prognostic factor for patients 
with RCC.  Although various risk stratification systems have been described, none of them 
has been accepted as the standard of care.  This study aims to recruit those patients who are 
at a potentially relatively increased risk of disease recurrence.  Therefore, the target patients 
in this study are able to be considered patients at high risk of recurrent RCC. 
According NCCN Guidelines v1.2014, adjuvant treatment after nephrectomy currently has 
no established role in patients with renal cell cancer who have undergone a complete 
resection of their tumor. No systemic therapy has yet been shown to reduce the likelihood of 
relapse. Randomized trials comparing adjuvant interferon alpha or high-dose interleukin (IL-
2) or cytokines combinations with observation alone in patients who had locally advanced, 
completely resected RCC showed no delay in time to relapse or improvement in survival 
with adjuvant therapy. Observation remains standard care after nephrectomy, and eligible 
patients should be offered enrolled in randomized clinical trials. 
Without an established adjuvant treatment for patients with high risk of recurrence of their 
renal cell cancer after nephrectomy and observation or participation in clinical study as 
recommended standard; several placebo-controlled, randomized, double blind studies are 
currently ongoing in this indication (http://clinicaltrials.gov), which is ethically justifiable 
and necessary to meet regulatory standards for drug approval. 
2. TRIAL OBJECTIVES 
2.1. Primary Objective 
• To demonstrate an improvement in disease free survival (DFS) in patients at high risk 
of recurrent RCC randomly assigned to adjuvant axitinib (Arm A) vs. Placebo (Arm 
B) after nephrectomy. 


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2.2. Secondary Objectives 
• Compare OS associated with Arm A to that associated with Arm B 
• Assess safety/toxicity profile of administration of axitinib 
3. TRIAL DESIGN 
This is a prospective, randomized, double-blind placebo controlled Phase 3 trial of oral 
axitinib starting at 5 mg twice daily vs. placebo given for up to 3 years, with a minimum of 1 
year. The dose may be increased or decreased depending on individual patient tolerance of 
axitinib.   
A total of approximately 700 patients will be randomized in a 1:1 ratio between axitinib vs 
placebo.  Patients should begin study treatment within 7 days after randomization.  
Randomization will occur no sooner than 4 weeks post-nephrectomy and no later than 12 
weeks post-nephrectomy. 
Follow-up for recurrence (distant or local recurrence of RCC) or occurrence of a secondary 
malignancy (occurrence of a second primary cancer other than RCC) must be collected at 
each clinic visit as per protocol.  All patients will be followed up (regardless of the duration 
of treatment) until the time for the final analysis, every 16 weeks for the first 3 years from 
initiation of study treatment (also, at the end of treatment) and every 6 months thereafter for 
the remainder of the follow-up period, by clinic visit (See Section 6.4 for further details). 
All patients will be followed up for OS status (regardless of the duration of treatment) every 
16 weeks until the time for final DFS analysis.  Survival status can be ascertained by 
telephone contact.  At the time of final DFS analysis, OS results will be analyzed and 
summarized.  
Study Scheme: 
 
 
 
 
 
4. SUBJECT SELECTION 
The following eligibility criteria are designed to select patients for whom protocol treatment 
is considered appropriate.  All relevant medical and non-medical conditions should be taken 
into consideration when deciding whether this protocol is suitable for a particular patient.   
Arm A: axitinib 
Arm B: placebo 
Randomization 
Follow-up 
Treatment: Up to 3 years, with 
a minimum of 1 year 


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4.1. Inclusion Criteria 
Patients must be newly-diagnosed RCC and treated by nephrectomy (complete or partial) and 
patients must meet all of the following inclusion criteria to be eligible for enrollment into the 
trial: 
1. Patients must have no evidence of macroscopic residual disease or metastatic disease. 
2. Male or female, age ≥18 years (age ≥20 years in Japan, Korea and Taiwan, age ≥18 
years and ≤ 65 years in India). 
3. Patients must be diagnosed with one of the following based on American Joint 
Committee on Cancer (AJCC) TNM staging version 2010 29, Eastern Collaborative 
Oncology Group (ECOG) performance status (PS). Any Fuhrman grades are eligible. 
The patient risk groups will be as follows. Group a will be closed for further 
enrollment, to keep the number of patients of groups b, c, and d with about 90% or 
more: 
a. 
pT2, pN0 or pNx, M0 and ECOG PS 0-1 
b. pT3, pN0 or pNx, M0 and ECOG PS 0-1 
c. 
pT4, pN0 or pNx, M0 and ECOG PS 0-1 
d. Any pT, pN1, M0 and ECOG PS 0-1 
 
4. Patients must have histologically confirmed preponderant, defined as >50%, clear cell 
RCC. 
5. Patients must not have received any previous systemic (includes chemotherapeutic, 
hormonal, or immunotherapeutic) treatment for RCC. 
6. Patients must not have received any previous anti-angiogenic treatment. 
7. Patients must have adequate organ function defined as:  
• Absolute neutrophil count (ANC) ≥1500 cells/mm3. 
• Platelets ≥75,000 cells/mm3. 
• Hemoglobin (Hgb) ≥9.0 g/dL. 
• AST and ALT ≤2.5 x upper limit of normal (ULN). 
• Total bilirubin ≤1.5 x ULN. 
• Serum creatinine (Scr) ≤1.5 x ULN or calculated creatinine clearance (Clcr) ≥30 
mL/min (by the Cockcroft-Gault equation*). 
* For males; the Cockcroft-Gault equation, using Scr : Clcr (mL/min) = (140 - 
Age in years) × weight (in kilograms) / [72 × Scr (in mg/dL)] 
The calculated Clcr should be multiplied by 0.85 to adjust for female gender. 
• Urinary protein <2+ by urine dipstick.  If dipstick is ≥2+ then a urine protein: 
urine creatinine ratio (UPC) should be done and the patient may enter only if UPC 
is < 2.0. 
 


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8. At screening, no evidence of preexisting uncontrolled hypertension as documented by 
2 blood pressure (BP) readings taken at least 1 hour apart in the seated position after 
the patient has been sitting quietly for 5 minutes.  The systolic blood pressure (sBP) 
readings must be ≤140 mm Hg, and the diastolic blood pressure (dBP) readings must 
be ≤90 mm Hg.  Patients whose hypertension is controlled by antihypertensive 
therapies are eligible. 
9. Women of childbearing potential and men must use adequate contraception during 
the study and for 6 months after discontinuing or completing study treatment.  
Acceptable contraception for women include implants, injectables, combined oral 
contraceptives, intrauterine devices (IUDs), sexual abstinence, or a partner who has 
been vasectomized for at least 6 months.  Acceptable contraception for a male 
includes having had a vasectomy for at least 6 months, sexual abstinence, or condoms 
plus spermicide. 
10. Signed and dated informed consent document (ICD) indicating that the patient (or 
legally acceptable representative) has been informed of all pertinent aspects of the 
trial prior to enrollment. 
11. Willingness and ability to comply with scheduled visits, treatment plans, laboratory 
tests, and other study procedures. 
4.2. Exclusion Criteria 
Patients presenting with any of the following will not be included in the trial: 
1. Histologically undifferentiated carcinomas, sarcomas, collecting duct carcinoma, 
lymphoma, or patients with any metastatic renal sites. 
2. Active bleeding (other than menstrual bleeding) at randomization. 
3. Diagnosis of any non-RCC malignancy within the 5 years from date of 
randomization, except basal cell carcinoma, squamous cell skin cancer, or in situ 
carcinoma of the cervix uteri that has been adequately treated with no evidence of 
recurrent disease for 12 months. 
4. Any of the following within the 12 months prior to study drug administration:  
myocardial infarction, uncontrolled angina, coronary/peripheral artery bypass graft, 
symptomatic congestive heart failure, cerebrovascular accident or transient ischemic 
attack and 6 months for deep vein thrombosis or pulmonary embolism. 
5. Gastrointestinal abnormalities including: 
• inability to take oral medication  
• requirement for intravenous alimentation 
• prior surgical procedures affecting absorption including total gastric resection 
• treatment for active peptic ulcer disease in the past 6 months 


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• active gastrointestinal bleeding, unrelated to cancer, as evidenced by 
hematemesis, hematochezia or melena in the past 3 months without evidence of 
resolution documented by endoscopy or colonoscopy 
• malabsorption syndromes 
• chronic diarrhea that persists at Grade 3 or 4 despite maximal medical therapy 
6. Major surgery <4 weeks, or radiation theapy <2 weeks, of starting the study treatment 
or incomplete healing of surgical or superficial wounds. 
7. Current use or anticipated need for treatment with drugs that are known potent 
CYP3A4/5 inhibitors (eg, grapefruit juice, ketoconazole, itraconazole, clarithromycin, 
atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, and telithromycin). 
8. Current use or anticipated need for treatment with drugs that are known CYP3A4/5 or 
CYP1A2 inducers (eg, rifampin, dexamethasone, phenytoin, carbamazepine, 
rifabutin, rifapentin, phenobarbital, and St. John’s wort). 
9. Active seizure disorder or evidence of brain metastases, spinal cord compression, or 
carcinomatous meningitis. 
10. A serious uncontrolled medical disorder or active infection that would impair their 
ability to receive study treatment. 
11. Known human immunodeficiency virus (HIV) or acquired immunodeficiency 
syndrome (AIDS)-related illness. 
12. Pregnancy or breastfeeding.  Urinary pregnancy test should be performed by sites on 
female patients who have not experienced at least one consecutive year of 
amenorrhea without ovarian dysfunction, or have been taking hormonal therapy, or 
have been rendered surgically sterile.  If positive, serum pregnancy test should be 
performed at central laboratories. All female patients of childbearing potential must 
have a negative pregnancy test within the 14 days prior to date of randomization.  
(Definition of surgical sterilization: patients who underwent hysterectomy or bilateral 
oophorectomy, or bilateral tubal ligation) 
13. Dementia or significantly altered mental status that would prohibit the understanding 
or rendering of informed consent and compliance with the requirements of this 
protocol. 
14. Other severe acute or chronic medical or psychiatric condition or laboratory 
abnormality that may increase the risk associated with study participation or study 
drug administration, or may interfere with the interpretation of study results, and in 
the judgment of the investigator would make the patient inappropriate for entry into 
this study. 
15. Receipt of any investigational oncology or, approved or investigational 
anti-angiogenic agent prior to study entry. 


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16. Current treatment on another therapeutic clinical trial.  Supportive care trials or 
non-treatment trials, eg, Patient Reported Outcomes (PRO) methods studies, are 
allowed. 
4.3. Randomization Criteria  
Patients must be randomized no earlier than 4 weeks and no later than 12 weeks after 
nephrectomy and treatment should be started within 7 days after randomization.  Patient 
eligibility must be confirmed by independent review committee (IRC) assessment of imaging 
by a sponsor designated center prior to randomization. 
Patients must be randomized based on the assessment by the IRC when there is a discrepancy 
between the local and the IRC imaging review. 
A centralized system will be used to assign patient numbers and randomize patients into 
blinded study drug: axitinib, or blinded placebo identical in appearance to the active study 
drug. 
After a patient has provided written informed consent and has completed the necessary 
screening assessments, the clinical site must contact a centralized internet/telephone 
registration system (IWRS/IVRS), to enroll the patient into study. 
For those patients who failed screening, the reason for screen failure should be entered in the 
source documentation.  The following information should also be collected in the source 
documents: Patient age, sex, ECOG PS, tumor size (eg, T1, T2, T3), nodal disease (Yes/No), 
metastatic disease (Yes/No), histological type (eg, clear cell).  
At the time of registration, the clinical site staff must provide site and patient identifiers and 
demographic information.  The registration system will assign a unique patient identification 
number.  The system will also be used to assign blinded study drug bottles.  Patients will be 
randomized to one of two arms: 
Arm A: axitinib 5 mg BID taken orally (doses should be taken approximately 12 hours apart 
continuous dosing) 
Arm B: Placebo tablets BID taken orally  
Patients will be stratified by: 
1. Risk group 
a. 
pT2, pN0 or pNx, M0 and ECOG PS 0-1 
b. pT3, pN0 or pNx, M0 and ECOG PS 0-1 
c. 
pT4, pN0 or pNx, M0 and ECOG PS 0-1 
d. Any pT, pN1, M0 and ECOG PS 0-1 
2. Country 


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Eligible patients will be randomized in a 1:1 ratio to one of the two treatments using the 
registration system.  Patients in risk group a or b will be stratified by risk group and by 
country.  Patients in risk group c or d will be stratified by risk group only.   
Randomization shall continue until a minimum of 10% of subjects are represented in this 
study from groups c and d.  Risk group a will be closed for from further enrollment, to keep 
the number of patients of risk groups b, c, and d with about 90% or more. 
4.4. Life Style Guidelines  
During the study female patients of childbearing potential must take precautions to prevent 
pregnancy since the effects on the fetus are unknown.  Male patients with partners of 
childbearing potential must take precautions to prevent pregnancy of the partner since the 
effects of these drugs on sperm are unknown.  These restrictions should remain in force for 6 
months from the last dose of investigational agent.  Drug interaction studies with oral 
contraceptives have not been performed, so barrier methods of contraception or abstinence 
should be considered.  Adequate contraception should be discussed with the investigator 
before the treatment start and should be in agreement with local law. 
5. TRIAL TREATMENTS 
5.1. Allocation to Treatment 
Axitinib for up to 3 years, with a minimum of 1 year until recurrence, occurrence of a 
secondary malignancy, significant toxicity, or withdrawal of consent. 
OR 
Placebo for up to 3 years, with a minimum of 1 year until recurrence, occurrence of a 
secondary malignancy, significant toxicity, or withdrawal of consent. 
5.2. Breaking the Blind  
At the initiation of the trial, the trial site will be instructed on the method for breaking the 
blind.  The method will be an electronic process.  Blinding codes should only be broken in 
emergency situations for reasons of patient safety, or if the patient has a confirmed 
recurrence or occurrence of a secondary malignancy with limited alternative treatment option 
and knowledge of study drug is required to facilitate further treatment decision. For those 
with suspected recurrence, the site must await results from the Independent Review 
Committee (IRC). The decision to break the blind must be approved by the Sponsor prior to 
doing so. When the blinding code is broken, the reason must be fully documented in the site 
source document. 
5.3. Drug Supplies 
In this clinical trial, study drug or investigational agent refers to axitinib and placebo. 


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5.3.1. Formulation and Packaging 
Axitinib will be supplied as 1 mg and 5 mg film-coated tablets for oral administration in 
light-protecting bottles.  Placebo will match all dose formulations.  
5.3.2. Preparation and Dispensing 
Axitinib and matching placebo will be dispensed as tablets in opaque plastic bottles to protect 
the compounds from light.  Axitinib is a hazardous drug (due to possible reproductive 
toxicity), and should be handled according to the recommended procedures described in the 
current edition of the American Society of Hospital Pharmacists (ASHP), Technical 
Assistance Bulletin on Handling Cytotoxic and Hazardous Drugs, American Hospital 
Formulary Service (AHFS) Drug Information (1999) and its references.  Procedures 
described in each institution’s pharmacy or hospital standard operating procedure manual 
should be followed when handling hazardous drugs. 
5.3.3. Administration 
Patients will receive blinded study drug: Axitinib or blinded matching placebo identical in 
appearance to the active study drug twice daily. 
Patients will receive a starting dose of 5 mg of axitinib or placebo twice daily taken orally 
with or without food.  Dose adjustments, including dose increase or dose reduction will be 
based on adverse events experienced by the individual patient.  Study drug will be taken 
beginning on Day 1 of the study.  Doses should be taken approximately 12 hours apart 
continuous dosing.  Patients should be instructed to take their doses at approximately the 
same times each day.  If a patient vomits or misses a dose, an additional dose should not be 
taken. The next prescribed dose should be taken at the usual time.  Missed or vomited doses 
must be indicated in the source documents and Case Report Forms (CRFs). Study drug will 
be administered in cycles of 4 weeks in duration. 
Patients who tolerate axitinib or placebo with no adverse events related to study drug above 
CTCAE Grade 2 for a consecutive 2-week period may have their dose increased by one dose 
level to maximum of 10 mg BID (unless the patient’s BP is >150/90 mm Hg or the patient is 
receiving antihypertensive medication).  The clinical judgment of the treating investigator 
should be exercised in titrating axitinib/placebo dose. 
Patients experiencing drug reaction should undergo dose modification as recommended in 
Section 5.3.4. 
Once the dosage is reduced, it can be uptitrated again. 
Concomitant medications that are known to substantially inhibit the enzyme, CYP3A4/5, 
should be avoided as much as medically possible on this study as in Section 5.5.1.  If a strong 
CYP3A4/5 inhibitor must be co-administered, based on investigator judgment, the dose of 
study drug (axitinib/placebo) should be decreased by one or more dose levels. 


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Table 2 
Available Axitinib/Placebo Dose Levels 
Dose Level 
Dose 
Dispensed As 
+2 
10 mg BID 
2 X 5 mg Tablets BID  
+1 
7 mg BID 
1 X 5 mg Tablet  BID + 2 X 1mg Tablets BID 
0 (Starting Dose) 
5 mg BID 
1 X 5 mg Tablet BID (twice daily) 
-1 
3 mg BID 
3 X 1 mg Tablets BID     
-2 
2 mg BID 
2 X 1 mg Tablets BID     
-3 
1 mg BID 
1 X 1 mg Tablet BID 
 
5.3.4. Dose Interruption and Reduction 
Adverse events and other symptoms will be graded according to the current CTCAE v4.0 
(See URL:  http://ctep.cancer.gov/reporting/ctc.html). 
5.3.4.1. Management of Axitinib/Placebo-Related Adverse Events 
This section contains management of adverse events except hypertension and proteinuria 
which are discussed in subsequent sections. 
The criterion for dose modification for study-drug-related adverse events is summarized in 
the table below: 
Table 3 
Criteria for Dose Modification for Axitinib/Placebo – Related Adverse 
Events Other Than Hypertension Or Proteinuria 
Related Adverse Events 
Intervention 
Grade 1 
Continue at same dose level. 
Grade 2*  
Continue at same dose level or decreased dose to one 
lower dose level.a) 
Grade 3* 
Interrupt dosing; re start at one or two lower dose level 
as soon as improvement to CTCAE Grade ≤1 or 
baseline.b)  Discontinue dosing in case of grade 3 
persisting for ≥ 2 weeks or grade 3 despite dose 
reduction to 1 mg BID. 
Grade 4 or RPLS** 
Discontinue dosing 
* Patients who have a grade 3 arterial event, grade 3 hemorrhagic event, grade 3 perforation/fistula, grade 3 
palmar-planter erythrodysesthesia syndrome (PPE), or persistent grade 2 PPE despite dose reduction to 1 mg 
BID, should be discontinued dosing.  
** Treatment interruption for patients with signs/symptoms of reversible posterior leukoencephalopathy (RPLS). 
RPLS is a neurological disorder which can present with headache, seizure, lethargy, confusion, blindness and 
other visual and neurologic disturbances. Mild to severe hypertension may be present. Magnetic resonance 
imaging is necessary to confirm the diagnosis of RPLS. In case of confirmed diagnosis discontinue 
permanently. 
a) Dose may be decreased to one lower dose level if the investigator considers it is difficult to continue 
treatment at same dose level. 
b) Dose may be decreased to two lower dose level if the investigator considers it is difficult to continue 
treatment at one lower dose level. 
 


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Dose may also be interrupted or decreased at the discretion of the investigator even if none of 
the above criteria applies. 
Guidelines for dose reductions for specific adverse events are provided in the following 
sections. 
5.3.4.2. Axitinib/Placebo Dose Reduction for Hypertension 
Patients treated with axitinib/placebo will be issued blood pressure cuffs (provided by 
Sponsor) for home monitoring and instructed to measure their blood pressure prior to taking 
each dose of study drug (twice daily) for the first 3 months, and once a week thereafter.  
Following dose modification of study drug or anti-hypertensive medication, or changes of 
anti-hypertensive medication, patients must restart blood pressure measurements prior to 
taking each dose of study drug for the first 3 months and once a week thereafter.  All BP 
measurements will be recorded in a diary by the patient themselves and brought to the nurse 
or study coordinator at each clinic visit.  Patients should be instructed by the study staff to 
contact their investigator immediately for guidance if their sBP rises above 150 mm Hg, or 
dBP rises above 100 mm Hg, or if they develop symptoms perceived to be related to elevated 
BP (eg, headache, visual disturbance).  See below for dose modifications for hypertension. 
New or additional antihypertensive therapy (See Section 5.5.1, Concomitant Medication) 
should be started if 2 BP readings, taken at site and separated by at least 5 minutes in the 
seated position after the patient has been sitting quietly for 5 minutes, show the following: 2 
sBP readings >150 mm Hg or 2 dBP readings  >100 mm Hg.  Alternately, the dose of 
existing antihypertensive medication(s) may be increased.  If the patient is already on 
maximal antihypertensive treatment, the axitinib/placebo dose should be reduced by 1 dose 
level. 
Patients who have 2 sBP readings, separated by at least 5 minutes, greater than 160 mm Hg, 
or 2 dBP readings, separated by at least 5 minutes in the seated position after the patient has 
been sitting quietly for 5 minutes, greater than 105 mm Hg, will have treatment with 
axitinib/placebo interrupted.  (Note: if axitinib/placebo is interrupted, patients receiving 
antihypertensive medications should monitor closely for hypotension and restart 
axitinib/placebo at one lower dose level as soon as BP is ≤150/100 mm Hg.  Plasma half-life 
of axitinib is 2-4 hours and BP usually decreases within 1-2 days following dose 
interruption.)  Treatment with axitinib/placebo should be restarted at 1 lower dose level as 
soon as the sBP reduces to less than or equal to 150 mm Hg and the dBP reduces to less than 
or equal to 100 mm Hg. 
Patients who develop recurrent systolic hypertension (2 BP readings separated by at least 
5 minutes show sBP >150 mm Hg) or recurrent dBP >100 mm Hg following previous 
axitinib/placebo dose reduction should undergo another dose reduction by one dose level.   
Patients removed from treatment for intolerable toxicity should still be followed with regular 
tumor assessments until recurrence or occurrence of a secondary malignancy or start of new 
treatment, and for survival thereafter. Guidance on dose interruption and reduction for 


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hypertension is summarized in the table below.  The BP readings stated in this table is based 
on BP measurement taken at the site. 
Table 4 
 Hypertension Management Plan for Axitinib/Placebo 
Degree of Blood Pressure Elevation 
Management 
Systolic Blood Pressure 
 
 
OR 
Diastolic Blood Pressure 
 
If not on maximal antihypertensive 
treatment, institute new or additional 
antihypertensive medication* and 
maintain dose of axitinib/placebo.  
If on maximal antihypertensive 
treatment, reduce axitinib/placebo to 
one lower dose level. 
2 BP readings separated by at 
least 5 minutes show sBP 
>150 mm Hg 
2 BP readings separated by 
at least 5 minutes show dBP 
>100 mm Hg 
2 BP readings separated by at 
least 5 minutes show sBP 
>160 mm Hg  
 
 
OR 
2 BP readings separated by 
at least 5 minutes show dBP 
>105 mm Hg  
Interrupt dosing**; 
Adjust antihypertensive medication; 
As soon as BP is less than or equal to 
150/100 mm Hg, restart 
axitinib/placebo at one lower dose 
level.   
Recurrent hypertension 
following previous dose 
reduction (2 BP readings 
separated by at least 5 
minutes show sBP >150 mm 
Hg) 
 
OR 
Recurrent dBP >100 mm Hg 
(2 BP readings separated by 
at least 5 minutes) following 
previous dose reduction 
Repeat axitinib/placebo dose reduction 
by one lower dose level.   
* If no contraindication – consider preferred anti-hypertensive monotherapy: Angiotensin system inhibitors 
(ASI) or preferred combination anti-hypertensive therapy: Diuretic and angiotensin system inhibitor [please 
check local guidelines] 
Based on current international guidelines: ASI- Angiotensin Converting Enzyme (ACE) Inhibitor or 
Angiotensin receptor blocker; Diuretics; Beta-blocker or Calcium antagonists: All suitable and recommended 
for initiation + maintenance of antihypertensive treatment as monotherapy or in some combinations. Additional 
aspects for consideration within this study:  
- No drug-drug interaction between axitinib and ASI expected (e.g. enalapril, captopril, losartan, valsartan). 
Retrospective data [McKay et al.J Clin Oncol 32, 2014 (suppl 4; abstr 437)] indicate that ASI may improve 
outcome in patients with renal cell cancer. 
- No interference between axitinib and beta blockers (atenolol, metoprolol, labetalol), or diuretics 
(hydrochlorothiazide, furosemide) expected. 
- Not first choice based on potential interference with axitinib plasma level: calcium channel blockers 
(verapamil) and to a lesser extent nifedipine, nicardipine, and diltiazem.  
- Other calcium channel blockers (amlodipine, bepridil, felodipine) are less likely to interfere with axitinib 
plasma levels. 
** If axitinib/placebo is interrupted, patients receiving antihypertensive medications should be monitored 
closely for hypotension. Plasma half-life of axitinib is 2-4 hours and BP usually decreases within 1-2 days 
following dose interruption. 
 
5.3.4.3. Axitinib/Placebo Dose Reduction for Proteinuria 
• If dipstick shows ≥2+ proteinuria, perform UPC.  Dosing may continue while waiting for 
test results. 
• If UPC < 2.0 is reported, continue dosing at the same dose level. 


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• If UPC ≥ 2.0 is reported, hold dosing and repeat UPC (interval at investigator discretion) 
until UPC is < 2.0. Restart axitinib/placebo at the same dose or one lower dose level at 
discretion of the investigator.  Repeated UPC can be performed during treatment 
interruption at the site laboratory. 
• If UPC ≥ 2 despite dose reduction to 1 mg BID, discontinue dosing. 
Patients removed from treatment for intolerable toxicity should still be followed with regular 
tumor assessments until recurrence or occurrence of a secondary malignancy or start of new 
treatment, and for survival thereafter. 
5.3.4.4. Axitinib/Placebo Dose Interruption for Surgery or Surgical Procedures 
If a major surgery or an invasive intervention (eg, endoscopy) is required, treatment with 
axitinib/placebo must be interrupted at least 24 hours before the procedure and the patient BP 
should be monitored closely for hypotension.  Depending on the investigators assessment 
patients may resume axitinib/placebo 7 days after surgery/invasive intervention, assuming 
wound has completely healed and no wound healing complications (eg, delayed healing, 
wound infection or fistula). 
5.3.5. Compliance 
Patients will maintain diaries to include missed or changed doses.  Pill counts on returned 
study drug bottles should be performed. 
5.4. Drug Storage and Drug Accountability 
Axitinib/placebo will be supplied for the study.  Study drug will be shipped to the study sites. 
The investigator, or an approved representative (eg, pharmacist), will ensure that all 
axitinib/placebo is stored in a secured area, under recommended storage conditions and in 
accordance with applicable regulatory requirements.  Drug should be stored at controlled 
room temperature (ie, 15-30°C) and protected from light and moisture.  
To ensure adequate records, all axitinib/placebo will be accounted for in the CRFs and drug 
accountability inventory forms as instructed by sponsor.  Unless otherwise authorized by 
sponsor, at the end of the clinical trial all drug supplies unallocated or unused by the patients 
must be returned to sponsor or its appointed agent (eg, a contract research organization). 
Axitinib is considered a hazardous drug (due to possible reproductive toxicity), and should be 
handled according to the recommended procedures described in the current edition of the 
ASHP, Technical Assistance Bulletin on Handling Cytotoxic and Hazardous Drugs, AHFS 
Drug Information (1999) and its references.  Procedures described in each institution’s 
pharmacy or hospital standard operating procedure manual should be followed when 
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5.5. Prior/Concomitant Therapy 
5.5.1. Prior/Concomitant Medication 
No other chemotherapy or experimental anticancer medications will be permitted while the 
patient is on study.  Any disease requiring other forms of systemic anticancer therapy will be 
cause for discontinuation from study treatment.   
Patients may receive loperamide or other medications for treatment or prophylaxis of 
potential diarrhea.  Anti-inflammatory or narcotic analgesics may be offered as needed.  
Patients with fever or infection may undergo diagnostic tests and treated with antibiotics as 
appropriate and may receive therapeutic colony-stimulating factors as appropriate.  
Erythropoietic agents such as epoetin or darbepoetin may be used at the discretion of the 
treating investigator.  Packed red blood cell and platelet transfusions should be administered 
as clinically indicated.  Low-dose oral steroids (defined as <5 mg per day prednisone or 
equivalent), short course of oral steroids (defined as < 5 consecutive days or topical or 
inhaled steroids at any dose) may be taken during the study.   
Patients who need to be on anticoagulant therapy before or during study treatment should be 
treated with low molecular weight heparin. If low dose heparin cannot be administered, the 
administration of coumadin or other coumarin derivatives or other anti-coagulants may be 
allowed; however, appropriate monitoring for bleeding risk including prothrombin 
time/international normalized ratio (PT/INR) should be performed. 
In vitro studies with human liver microenzymes and recombinant CYP enzymes indicated 
that axitinib metabolism was primarily mediated by the drug-metabolizing enzyme 
CYP3A4/5, and to a lesser extent by CYP1A2.  Additionally, the drug also undergoes 
N-glucuronidation in liver microsomes of some species.  Clinically, there is likelihood that 
axitinib plasma concentrations may be increased in the presence of co-administered potent 
inhibitors of the CYP3A4/5 and glucuronosyltransferase enzymes.  In a healthy volunteer 
study, ketoconazole, a potent CYP3A4/5 inhibitor, produced a 2-fold increase in plasma 
exposure and a 1.5-fold increase in peak plasma concentration of axitinib. Therefore a 
potential exists for drug-drug interactions with CYP3A4/5 inhibitors such as grapefruit juice, 
ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, 
ritonavir, saquinavir, and telithromycin.  Caution should be exercised in patients receiving 
axitinib in combination with these and other potent CYP3A4/5 inhibitors until appropriate 
clinical drug interaction studies are performed.  If a strong CYP3A4/5 inhibitor must be co-
administered, based on investigator judgment, the dose of study drug (axitinib/placebo) 
should be decreased by one or more dose levels. 
Axitinib metabolism may be induced in patients taking CYP3A4/5 or CYP1A2 inducers 
(rifampin, dexamethasone, phenytoin, carbamazepine, rifabutin, rifapentin, phenobarbital, 
and St. John’s wort) and this may reduce axitinib plasma concentrations.  Patients who 
require concomitant treatment with potent CYP3A4/5 or CYP1A2 inducers are not eligible 
for the study.  Since CYP1A2 is also known to be induced in chronic smokers, there is 
likelihood that axitinib plasma concentrations may be reduced in these individuals.  (Note: 
these patients are not excluded from enrolment, however.) 


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The ability of axitinib to increase concentrations of coadministered drugs was also 
investigated in studies with human liver microsomes.  At expected therapeutic plasma 
concentrations (0.01 to 1.0 μg/mL), axitinib appears most likely to inhibit the drug 
metabolizing enzymes CYP1A2 and CYP2C8, 2 enzymes not frequently observed as 
predominant drug metabolizing enzymes.  Theophylline, and tacrine are among the few drugs 
whose plasma concentrations are likely to be increased by axitinib. 
Axitinib is highly bound to proteins in human plasma (99.5% bound at concentrations 
between 0.2 to 20 μg/mL).  Therefore, drug interactions with other agents that are also highly 
bound to plasma proteins are a possibility. 
Axitinib is not likely to have drug-drug interactions with commonly used antihypertensive 
agents belonging to the class of ACE inhibitors including angiotensin II receptor antagonists 
(enalapril, captopril, losartan, valsartan), beta-blockers (atenolol, metoprolol, labetalol), or 
diuretics (hydrochlorothiazide, furosemide).  Within the class of calcium channel blockers, 
verapamil, and to a lesser extent nifedipine, nicardipine, and diltiazem have a potential for 
increasing axitinib plasma concentrations, due to CYP3A4/5 inhibition and should not be 
used as first choice in antihypertensive treatment.  Other calcium channel blockers 
(amlodipine, bepridil, felodipine) are less likely to raise axitinib plasma levels. 
The above information is based on preclinical data from studies using human and animal 
metabolizing enzyme systems.  
All prior/concomitant medications and blood products, as well as interventions (eg, analgesic 
use or paracentesis) received by patients from the time the patient has signed informed 
consent until 28 days after last treatment will be recorded on the CRF.  Anti-tumor therapy 
should be recorded even after 28 days after last treatment. 
5.5.2. Concomitant Radiotherapy 
Investigators are encouraged to await the result of the IRC assessment before making 
treatment decisions for patients who require palliative radiotherapy because of suspected 
recurrence or occurrence of a secondary malignancy unless clinical considerations require 
immediate intervention eg, in the case of brain metastases.  In the event that an investigator 
determines recurrence or occurrence of a secondary malignancy based on local imaging 
and/or local histo-/cytopathology reports, the patient must continue to receive tumor 
assessments until the IRC determines recurrence or occurrence of a secondary malignancy.  
6. TRIAL PROCEDURES 
6.1. Screening 
 
 
 


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Figure 3 Screening Procedures 
 
 
 
 
 
 
6.1.1. Screening Procedures between Nephrectomy and Starting Treatment 
One rescreening is acceptable.  Patient with screening values/findings outside ranges 
described in the protocol may, at the discretion of the investigator, have one repeat 
determination performed and if the repeat value satisfies the criterion they may continue in 
the screening process. Only the specific out of range value/finding should be repeated (not 
the entire panel). 
a. Medical history including oncologic history, history of other disease processes (active 
or resolved), signs and symptoms, concomitant medications and treatments, illnesses 
and demographics. 
b. Local histopathology confirmation of eligibility is required. 
c. Pre-surgery images are requested, if available or whenever possible should be 
submitted for IRC review. 
d. ECOG PS ascertained at the time of nephrectomy (just prior to nephrectomy) is 
desired.   
e. Local and IRC review of tumor imaging including CT or MRI of the brain, chest, 
abdomen and pelvis and other applicable sites of disease.  CT scans are expected to 
be with intravenous and/or oral contrast.  CT or MRI of the chest, abdomen and 
pelvis must be performed at least 3 weeks after nephrectomy.  Results of the IRC 
assessment must be awaited before randomizing patients.  Thus, images should be 
submitted for IRC review before Week 8 post-nephrectomy to allow for return of the 
results before Week 12 and in the event a repeat scan is needed.  Brain CT or MRI 
within 12 weeks prior to randomization is acceptable regardless of whether it is 
before or after nephrectomy.  Bone scan (either Tc-99 or positron emission 
tomography (FDG-PET)) can be performed if clinically indicated. 
6.1.2. Screening Procedures Within 2 Weeks Prior to Randomization 
a. Physical examination of major body systems. 
Week 12 
Week 10 
Week 8 
Week 3 
Week 0 
*: IRC review of imaging to be returned within 2 weeks post submission of images. 
**: Randomization will occur no sooner than 4 weeks post-nephrectomy and no later than 12 weeks post-
nephrectomy. This figure shows the latest case after nephrectomy.  Study treatment should be started within 7 
days after randomization. 
 
Physical Exam, 
Body weight, height, 
Laboratory test, 
ECG, Vital 
Post- nephrectomy Imaging* 
Nephrectomy 
Randomization** 


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b. Body weight, height and vital signs (temperature, 2 BP readings separated by at least 
1 hour, pulse rate). 
c. Laboratory tests. 
• Hematology: Hgb, white blood cell count (WBC), ANC, lymphocyte count and 
platelet count. 
• Chemistry: Total bilirubin, AST, ALT, alkaline phosphatase, albumin, total 
protein, LDH, sodium, potassium, chloride, calcium, phosphate, BUN/Urea, 
creatinine, glucose. 
• Urine dipstick for protein (patients with ≥2+ protein will have UPC). 
• Pregnancy test, if applicable. Urine pregnancy test will be conducted at sites for 
females of childbearing potential only. If positive, then serum test should be 
conducted at central laboratories. 
d. Triplicate 12 lead ECGs to be performed two weeks prior to randomization.  Three 
consecutive 12 lead ECGs (with a 10 second rhythm strip) will be collected at 
screening to determine the mean QTc interval. If the QTc interval is prolonged 
(>500msec), the ECG should be re-read by a cardiologist at the site for confirmation. 
e. Assessment of concomitant medications and treatments. 
f. Study Registration/Randomization. 
6.2. Trial Period 
For the purposes of this study, unscheduled assessments may occur coincident with safety 
events, early discontinuation of study treatment, early study termination, suspected 
recurrence, or suspected occurrence of the secondary malignancy between protocol-specified 
study visits. 
6.2.1. Treatment Procedures First Cycle 
6.2.1.1. Day 1 
The following procedures must be performed pre-dose. It is not necessary to repeat the Day 1 
procedures if treatment is not started on the same day as randomization: 
a. Physical Examination of major body systems. 
b. Body weight and vital signs (temperature, BP, pulse rate). Patients who have 2 sBP 
readings, separated by at least 5 minutes, greater than 140 mm Hg, or 2 dBP readings, 
separated by at least 5 minutes, greater than 90 mm Hg, will not start treatment.   
c. ECOG PS. 


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d. Thyroid function tests: TSH, free T3, free T4. 
e. Assessment of adverse events. 
f. Assessment of concomitant medications and treatments. 
6.2.1.2. Day 15 
Assessments should be performed via telephone contact or visit.  In case of telephone contact, 
only adverse events assessment should be performed. 
a. Physical Examination of major body systems. 
b. Body weight and vital signs (temperature, 2 BP readings separated by at least 5 
minutes, pulse rate). 
c. Thyroid function tests: TSH (Free T3 and free T4 should be performed for any patient 
who has an elevated TSH at Day1 or the previous visit.)  Hypothyroidism should be 
treated per standard medical practice to maintain euthyroid state with a normal TSH. 
d. Assessment of adverse events. 
e. Assessment of concomitant medications and treatments. 
6.2.2. Treatment Procedures Subsequent Cycles 
Assessments other than tumor imaging should be done at Day 1 of every cycle (4 weeks) 
until Cycle 5 Day 1, then every 8 weeks thereafter starting from Cycle 7 Day 1. 
a. Physical examination of major body systems. 
b. Body weight and vital signs (temperature, 2 BP readings separated by at least 5 
minutes, pulse rate). 
c. ECOG PS. 
d. Laboratory tests. 
• Hematology: Hgb, WBC, ANC, lymphocyte count and platelet count. 
• Chemistry: Total bilirubin, AST, ALT, alkaline phosphatase, albumin, total 
protein, LDH, sodium, potassium, chloride, calcium, phosphate, BUN/Urea, 
creatinine, glucose. 
• Urine Dipstick for protein (patients with ≥2+ protein will have UPC). 
• Thyroid function tests: TSH.  Hypothyroidism should be treated per standard 
medical practice to maintain euthyroid state with a normal TSH (TSH, Free T3 


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and free T4 should be performed on the next visit for any patient who has an 
elevated TSH.). 
e. Tumor imaging including CT or MRI of the chest, abdomen, and pelvis should be 
performed every 16 weeks for the first 3 years from the initiation of study treatment.  
Additional imaging and/or local histo-/cytopathology confirmation, if clinically 
indicated, of potential disease sites should be performed whenever recurrence or 
occurrence of a secondary malignancy is suspected.  Brain CT or MRI with contrast 
or bone scan (confirmatory imaging in addition to bone scan may be required), if 
clinically indicated. 
f. Assessment of concomitant medications and treatments. 
g. Assessment of study drug compliance/accountability. 
h. Assessment of adverse events and tumor-related signs and symptoms. 
6.2.3. End of Study Treatment/Withdrawal from treatment Procedures 
At the end of the study or at withdrawal from treatment, the following procedures should be 
performed if they were not performed within 7 days of the end of the study or at withdrawal: 
a. Physical examination of major body systems. 
b. Body weight and vital signs (temperature, 2 BP readings separated by at least 5 
minutes, pulse rate). 
c. ECOG PS. 
d. Laboratory tests. 
• Hematology: Hgb, WBC, ANC, lymphocyte count and platelet count. 
• Chemistry: Total bilirubin, AST, ALT, alkaline phosphatase, albumin, total 
protein, LDH, sodium, potassium, chloride, calcium, phosphate, BUN/Urea, 
creatinine, glucose. 
• Urine Dipstick for protein (patients with ≥2+ protein will have UPC). 
• Thyroid function tests: TSH (Free T3 and free T4 should be performed for any 
patient who has an elevated TSH in the previous visit.) 
e. Tumor imaging including CT or MRI of the chest, abdomen, and pelvis and other 
applicable sites of disease.  Local histo-/cytopathology confirmation, if clinically 
indicated, of potential disease sites should be performed whenever recurrence or 
occurrence of a secondary malignancy is suspected.  Brain CT or MRI with contrast 
or bone scan if clinically indicated.  At the end of the study or at withdrawal, the 
tumor imaging should be performed if they were not performed within 8 weeks of the 


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end of the study or at withdrawal for patients who discontinue treatment for reasons 
other than disease progression. 
f. Assessment of concomitant medications and treatments. 
g. Assessment of study drug compliance/accountability.  Patients must return all used 
and unused study drug bottles to the clinical site. 
h. Assessment of adverse events and tumor-related signs and symptoms. 
6.3. 28 Days Post Treatment Follow-Up Visit 
Patients should continue to be evaluated up to 28 days after the last dose of study drug.  At 
the post-treatment follow-up visit, the following procedures should be performed: 
• Assessment of adverse events and tumor-related signs and symptoms. 
• Assessment of concomitant medications and treatments. 
During this period, the outcome of adverse events with a date of onset during the study 
period should be reevaluated, and any new adverse events should be recorded.  All serious 
adverse events, and those non-serious adverse events assessed by the investigator as possibly 
related to study drug, should continue to be followed even after patient withdrawal from 
study.  These adverse events should be followed until they resolve, or until the investigator 
assesses them to be “chronic” or “stable”.   
6.4. Recurrence or occurrence of secondary malignancy and Survival Follow-Up 
Follow-up for recurrence or occurrence of a secondary malignancy must be collected at each 
clinic visit as per protocol.  All patients will be followed up (regardless of the duration of 
treatment) until the time for final analysis, every 16 weeks for the first 3 years from initiation 
of study treatment (also, at the end of treatment) and every 6 months thereafter for the 
remainder of follow-up period*.  If new anti tumor therapy is initiated for either recurrence 
or occurrence of a secondary malignancy at any time during this period, this and all other 
pertinent data obtained should be recorded on the appropriate CRFs.  The final analysis of 
primary endpoint (DFS) will be performed when approximately 245 DFS events have been 
reached. 
* Patients who complete 3-year treatment will be followed up for DFS every 6 months from 
the date of CT or MRI at the end of study treatment.   
Patients who withdraw from treatment before DFS events will be followed up for DFS every 
16 weeks from the date of CT or MRI at the withdrawal.  After 3 years from initiation of 
study treatment, CT or MRI for DFS will be performed every 6 months from the first scan 
date that is performed after more than 3 years from initiation of study treatment. 
All patients will be followed up for OS status (regardless of the duration of treatment) 
approximately every 16 weeks from DFS events until the time for final DFS analysis.  
Survival status can be ascertained by telephone contact. 


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6.5. Patient Withdrawal 
Patients may withdraw from the treatment/trial at any time at their own request, or they may 
be withdrawn at any time at the discretion of the investigator or sponsor for safety, 
behavioral, or administrative reasons.  If a patient does not return for a scheduled visit, every 
effort should be made to contact the patient.  In any circumstance, every effort should be 
made to document patient outcome, if possible.  The investigator should inquire about the 
reason for withdrawal, request that the patient return all unused investigational product(s), 
request that the patient returns for a final visit, if applicable, and follow-up with the patient 
regarding any unresolved adverse events. 
6.5.1. Withdrawal from treatment 
Patients will be withdrawn from treatment in the case of: 
• Recurrence or occurrence of a secondary malignancy.  Investigators are encouraged 
to await the result of the IRC assessment before making treatment decisions unless 
clinical considerations require immediate intervention eg, in the case of brain 
metastases;  
• Unacceptable toxicity; 
• Need for anticancer therapy not specified in the protocol; 
• Congestive heart failure; 
• Repeated noncompliance; 
• Patient becomes pregnant; 
• Patient lost to follow-up; 
• Patient choice to withdraw from treatment (follow-up permitted by patient) 
If patients require >2 consecutive weeks of dose interruption, a discussion should be made in 
consultation with the medical monitor. 
Data to be collected for the end of study treatment/withdrawal from treatment are described 
in the End of Study Treatment/Withdrawal from treatment Procedures section (Section 
6.2.3).  Patients will be followed up for at least 28 days after the last dose of study drug for 
adverse events and concomitant medications and treatments.  
6.5.2. Withdrawal from trial 
If the patient withdraws from the trial and also withdraws consent for disclosure of future 
information, no further evaluations should be performed and no additional data should be 
collected.  Sponsor may retain and continue to use any data collected before such withdrawal 
of consent. 


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7. ASSESSMENTS 
7.1. Efficacy Assessments 
Local and the IRC imaging tumor assessments are to be performed between week 3-8 post-
nephrectomy.  Brain CT or MRI within 12 weeks prior to randomization is acceptable 
regardless of whether it is before or after nephrectomy. 
During the trial, local and the IRC imaging tumor assessments will be performed (regardless 
of the duration of treatment) every 16 weeks during the first 3 years of study (also, at the end 
of treatment) and every 6 months thereafter until the time for final analysis, or recurrence or 
occurrence of a secondary malignancy, whichever comes first.  
Investigators are encouraged to await the result of the IRC assessment before making 
treatment decisions for patients who require palliative radiotherapy because of suspected 
recurrence or occurrence of a secondary malignancy unless clinical considerations require 
immediate intervention eg, in the case of brain metastases.  In the event that an investigator 
determines recurrence or occurrence of a secondary malignancy based on local imaging 
reviews and/or local histo-/cytopathology reports, the patient must continue to receive tumor 
assessments until the IRC determines recurrence or occurrence of a secondary malignancy.  
Local and IRC imaging assessments at screening and during the trial will include CT or MRI 
of the brain, chest, abdomen and pelvis, and other applicable sites.  Further imaging 
techniques e.g., bone scan, are to be performed as clinically indicated if metastases are 
present or suspected. 
For patients who present with findings suggestive of a tumor recurrence or secondary 
malignancy, histo-/cytopathological confirmation of the diagnosis should be obtained except 
in patients whose suspicious lesions are deemed by the investigator not to be amenable to 
biopsy.  Such available local histo-/cytopathology reports should be submitted to the IRC for 
review in cases for which there is site confirmation of recurrence or occurrence of a 
secondary malignancy in the absence of IRC imaging confirmation.  For patients with an 
isolated, suspected intracranial recurrence, histologic documentation of recurrence in 
surgically accessible lesions is highly recommended, but not required. For such patients, 
document the recurrent disease using MRI or CT if MRI is not generally available or is 
contraindicated. 
The diagnosis of a recurrence or occurrence of a secondary malignancy can be made only 
when the imaging, clinical or pathology findings meet at least one of the following 
acceptance criteria: 
Lung 
a. Positive cytology or histology. 
b. Imaging evidence of lesions felt to be consistent with metastases. 
c. Proof of neoplastic pleural effusion should be established by cytology or pleural 
biopsy. 


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Liver 
a. Positive cytology or histology. 
b. New focal defects on MRI or CT that are enlarging in size as documented by at least 
a 4-week interval. 
c. Proof of neoplastic abdominal ascites established by cytology or histology. 
Central Nervous System 
a. Positive brain CT or MRI. 
b. Positive cerebral spinal fluid (CSF) cytology. 
Subcutaneous and Lymph Node Recurrence 
a. Positive histology. 
b. Progressively enlarging solid mass or node(s) as evidenced by two CT or MRI 
separated by at least a 4-week interval. 
•Nodal lesions must have a short axis diameter ≥10 mm to be considered enlarged. 
Skeletal 
a. Positive radiographic study such as bone scan (confirmatory imaging in addition to 
bone scan may be required). 
b. For a solitary lesion or equivocal finding on imaging, a positive histology.  
Other Organs 
a. Histology/aspiration cytology. 
b. Progressively enlarging solid mass or node(s) as evidenced by two CT or MRI 
separated by at least a 4-week interval.  
•Nodal lesions must have a short axis diameter ≥10 mm to be considered enlarged. 
c. Urethral obstruction in the presence of a mass as documented on CT or MRI. 
Anything not meeting the above criteria should be considered unacceptable for evidence of 
recurrence or occurrence of a secondary malignancy and should not be an indication to alter 
protocol therapy. 
7.1.1. Primary Endpoint 
DFS is defined as the time interval from the date of randomization to the first date of 
recurrence (distant or local recurrence of RCC) or the occurrence of a secondary malignancy  
or death.  The primary DFS analysis will be based on assessments by the IRC.  IRC will 
review all imaging data.  Additionally, in cases for which there is site confirmation of 
recurrence or occurrence of a secondary malignancy in the absence of IRC imaging 


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confirmation, available local histo-/cytopathology reports will also be reviewed by the IRC 
oncologist to determine confirmation of recurrence or occurrence of a secondary malignancy. 
Recurrence refers to relapse of the primary tumor in situ or at metastatic sites.  The date of 
recurrence or the occurrence of a secondary malignancy is defined as the date of the tumor 
scan or the date of collection of the histo-/cytopathological specimen (for patients who have 
site confirmation of recurrence or occurrence of secondary malignancy in the absence of IRC 
imaging confirmation) that demonstrated unequivocal recurrence or a secondary malignancy 
according to protocol criteria.  If both imaging and histo-/cytopatholigical confirmation of 
recurrence or sencondary malignancy are available, the earlier of the two dates will be 
considered.   
For patients with no DFS event, DFS time will be censored at the date of the last scan prior to 
the time for the analyses.  Patients alive who do not have post-baseline disease assessments 
will have their DFS times censored at randomization.  For patients receiving further 
anti-tumor therapy prior to recurrence or occurrence of a secondary malignancy or death, 
DFS will be censored on the date of the last scan prior to taking the anti-tumor medication.  
Patients who miss 2 or more consecutive tumor scans immediately followed by an event will 
be censored at the date of the last objective tumor assessment prior to the missing/not 
readable scans. 
7.1.2. Secondary Endpoints 
OS is defined as the time from the date of randomization to the date of death due to any 
cause.  In the absence of confirmation of death, survival time will be censored at the last date 
the patient is known to be alive.  Patients lacking data beyond randomization will have their 
survival times censored at randomization.  
7.2. Safety Assessments 
7.2.1. Adverse Events 
Assessment of adverse events will include: type, incidence, severity (graded by the National 
Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE], 
Version 4.0), timing, seriousness, and relatedness; and laboratory abnormalities. 
Baseline tumor-related signs and symptoms will be recorded as adverse events during the 
trial if they worsen in severity or increase in frequency. 
7.2.2. Laboratory Safety Assessments 
Hematology and blood chemistry will be drawn at the time points described in the Schedule 
of Activities and analyzed at central laboratories (Refer to Appendix 1).  Investigators may 
have additional blood tests performed for the purpose of planning treatment administration, 
dose modification, or following adverse events and should be repeated as clinically needed.  
PT/INR should be performed to monitor patients receiving concomitant warfarin or other 
anti-coagulants and when clinically indicated. 


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Thyroid Function Tests (TSH, free T3 and free T4) should be performed for all patients at 
baseline (Cycle 1Day 1 pre-dose).  Subsequently TSH should be done at Cycle 1 Day 15, 
Cycle 2 Day 1, Cycle 3 Day 1, Cycle 4 Day 1, Cycle 5 Day 1, then every 8 weeks thereafter 
starting from Cycle 7 Day 1. TSH, free T3, free T4 should be performed on the next visit for 
any patient who has an elevated TSH in the previous visit.  Hypothyroidism should be treated 
per standard medical practice to maintain euthyroid state with a normal TSH. 
7.2.3. Other Safety Assessments 
Physical examination: A physical examination including, but not limited to, general 
appearance, head, skin, neck, eyes, ears, nose, mouth, throat, breast, lungs, heart, abdomen, 
back, lymph nodes, extremities, thyroid, musculoskeletal, pulses and nervous system will be 
performed.  The physical examination will include examination of known and suspected sites 
of disease.   
Height and body weight: Height will be recorded at screening visit only.  Body weight will 
also be recorded at the start of each 4 week period. 
Vital Signs: Measurements will be made of temperature, BP and pulse rate.  2 BP readings 
should be taken at least 5 minutes apart in the seated position after the patient has been sitting 
quietly for 5 minutes.  
All patients will be issued a blood pressure monitor and blood pressure measurement diary.  
Patients will be asked to record their blood pressure measurements prior to taking each dose 
of study drug (twice daily) for the first 3 months, and once a week thereafter.  Following 
dose modification of study drug or anti-hypertensive medication, or changes of anti-
hypertensive medication, patients should restart blood pressure measurements prior to taking 
each dose of study drug for the first 3 months and once a week thereafter.  Patients should 
record all blood pressure measurements in their patient diary.  BP readings should be taken in 
the seated position after the patient has been sitting quietly for 5 minutes.  Patients should be 
instructed to inform the investigator immediately if their sBP rises above 150 mm Hg, dBP 
rises above 100 mm Hg, or if they develop symptoms perceived to be related to elevated BP 
(eg, headache, visual disturbance). 
ECOG PS: The ECOG PS scale will be used (Appendix 2).  Evaluation of ECOG PS at 
screening should reflect the patient condition just prior to nephrectomy.   
All safety assessments should be repeated as clinically needed. 
8. Adverse Event Reporting 
8.1. Adverse Events 
All observed or volunteered adverse events regardless of treatment group or suspected causal 
relationship to the investigational product(s) will be reported as described in the following 
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For all adverse events, the investigator must pursue and obtain information adequate both to 
determine the outcome of the adverse event and to assess whether it meets the criteria for 
classification as a serious adverse event (See Section 8.5) requiring immediate notification to 
sponsor or its designated representative.  For all adverse events, sufficient information should 
be obtained by the investigator to determine the causality of the adverse event.  The 
investigator is required to assess causality.  For adverse events with a causal relationship to 
the investigational product, follow-up by the investigator is required until the event or its 
sequelae resolve or stabilize at a level acceptable to the investigator, and sponsor concurs 
with that assessment. 
8.2. Reporting Period 
Serious adverse events require immediate notification to sponsor or its designated 
representative beginning from the time that the patient provides informed consent, which is 
obtained prior to the patient’s participation in the clinical trial, ie, prior to undergoing any 
trial-related procedure and/or receiving investigational product, through and including 
28 calendar days after the last administration of the investigational product.  Any serious 
adverse event occurring any time after the reporting period must be promptly reported if a 
causal relationship to investigational product is suspected.  
Non-serious adverse events should be recorded from the time the patient has taken at least 
one dose of trial treatment through last patient visit.  
If a patient begins a new anticancer therapy, the adverse event reporting period for 
non-serious adverse events ends at the time the new treatment is started.  Death must be 
reported if it occurs during the serious adverse event reporting period after the last dose of 
investigational product, irrespective of any intervening treatment. 
8.3. Definition of an Adverse Event 
An adverse event is any untoward medical occurrence in a clinical investigation patient 
administered a product or medical device; the event need not necessarily have a causal 
relationship with the treatment or usage.  Examples of adverse events include but are not 
limited to:   
• Abnormal test findings; 
• Clinically significant symptoms and signs; 
• Changes in physical examination findings; 
• Hypersensitivity; 
Additionally, they may include the signs or symptoms resulting from: 
• Drug overdose; 
• Drug withdrawal; 


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• Drug abuse; 
• Drug misuse; 
• Drug interactions; 
• Drug dependency; 
• Exposure In Utero. 
Worsening of signs and symptoms of the malignancy under trial should be reported as 
adverse events in the appropriate section of the CRFs.  Disease progression assessed by 
measurement of malignant lesions on radiographs or other methods should not be reported as 
adverse events.  See description of Serious Adverse Events in Section 8.5 with respect to 
disease progression. 
8.4. Abnormal Test Findings 
The criteria for determining whether an abnormal objective test finding should be reported as 
an adverse event are as follows:  
• Test result is associated with accompanying symptoms; and/or 
• Test result requires additional diagnostic testing or medical/surgical intervention; 
and/or 
• Test result leads to a change in trial dosing or discontinuation from the trial, 
significant additional concomitant drug treatment, or other therapy; and/or 
• Test result is considered to be an adverse event by the investigator or sponsor. 
Merely repeating an abnormal test, in the absence of any of the above conditions, does not 
constitute an adverse event.  Any abnormal test result that is determined to be an error does 
not require reporting as an adverse event. 
8.5. Serious Adverse Events 
A serious adverse event or serious adverse drug reaction is any untoward medical occurrence 
at any dose that: 
• Results in death; 
• Is life-threatening (immediate risk of death); 
• Requires inpatient hospitalization or prolongation of existing hospitalization; 
• Results in persistent or significant disability/incapacity; 


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• Results in congenital anomaly/birth defect. 
Progression of the malignancy under trial (including signs and symptoms of progression) 
should not be reported as a serious adverse event unless the outcome is fatal during the trial 
or within the safety reporting period.  Hospitalization due to signs and symptoms of disease 
progression should not be reported as serious adverse event.  If the malignancy has a fatal 
outcome within the safety reporting period, then the event leading to death must be recorded 
as an adverse event and as a serious adverse event with CTCAE Grade 5 (See Section 8.7, 
Severity Assessment).  Any histopathologically confirmed secondary malignancy must be 
reported as SAE. 
Medical and scientific judgment should be exercised in determining whether an event is an 
important medical event.  An important medical event may not be immediately 
life-threatening and/or result in death or hospitalization.  However, if it is determined that the 
event may jeopardize the patient and/or may require intervention to prevent one of the other 
outcomes listed in the definition above, the important medical event should be reported as 
serious. 
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; 
or development of drug dependency or drug abuse.1  
8.6. Hospitalization 
Adverse events reported from clinical trials associated with hospitalization or prolongation of 
a hospitalization are considered serious.  Any initial admission (even if less than 24 hours) to 
a healthcare facility meets these criteria.  Admission also includes transfer within the hospital 
to an acute/intensive care unit (eg, from the psychiatric wing to a medical floor, medical floor 
to a coronary care unit, neurological floor to a tuberculosis unit). 
Hospitalization does not include the following: 
• Rehabilitation facilities; 
• Hospice facilities; 
• Respite care (eg, caregiver relief); 
• Skilled nursing facilities; 
• Nursing homes; 
• Routine emergency room admissions; 
• Same day surgeries (as outpatient/same day/ambulatory procedures). 
                                                 
1 21CFR 312.32 


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Hospitalization or prolongation of hospitalization in the absence of a precipitating, clinical 
adverse event is not in itself a serious adverse event.  Examples include:  
• Admission for treatment of a preexisting condition not associated with the 
development of a new adverse event or with a worsening of the preexisting condition 
(eg, for work-up of persistent pre-treatment lab abnormality); 
• Social admission (eg, patient has no place to sleep); 
• Administrative admission (eg, for yearly physical exam); 
• Protocol-specified admission during a clinical trial (eg, for a procedure required by 
the trial protocol); 
• Optional admission not associated with a precipitating clinical adverse event (eg, for 
elective cosmetic surgery); 
• Pre-planned treatments or surgical procedures should be noted in the baseline 
documentation for the entire protocol and/or for the individual patient; 
• Admission exclusively for the administration of blood products. 
Diagnostic and therapeutic non-invasive and invasive procedures, such as surgery, should not 
be reported as adverse events.  However, the medical condition for which the procedure was 
performed should be reported if it meets the definition of an adverse event.  For example, an 
acute appendicitis that begins during the adverse event reporting period should be reported as 
the adverse event, and the resulting appendectomy should be recorded as treatment of the 
adverse event. 
8.7. Severity Assessment 
If required on the adverse event CRFs, the investigator will use the following definitions of 
severity in accordance with National Cancer Institute Common Terminology Criteria for 
Adverse Events (CTCAE) Version 4.0 to describe the maximum intensity of the adverse 
event.   
GRADE 
Clinical Description of Severity 
0 
No Change from Normal or Reference Range (This grade is not included in the 
Version 4.0 document but may be used in certain circumstances). 
1 
MILD Adverse Event 
2 
MODERATE Adverse Event 
3 
SEVERE Adverse Event 
4 
LIFE-THREATENING OR DISABLING Adverse Event 
5 
DEATH RELATED TO Adverse Event 
 
Note the distinction between the severity and the seriousness of an adverse event.  A severe 
event is not necessarily a serious event.  For example, a headache may be severe (interferes 


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significantly with patient's usual function) but would not be classified as serious unless it met 
one of the criteria for serious adverse events, listed above. 
8.8. Causality Assessment 
The investigator’s assessment of causality must be provided for all adverse events (serious 
and non-serious).  An investigator’s causality assessment is the determination of whether 
there exists a reasonable possibility that the investigational product caused or contributed to 
an adverse event.  If the investigator’s final determination of causality is unknown and the 
investigator does not know whether or not investigational product caused the event, then the 
event will be handled as “related to investigational product” for reporting purposes.  If the 
investigator's causality assessment is “unknown but not related to investigational product,” 
this should be clearly documented on trial records.   
In addition, if the investigator determines a serious adverse event is associated with trial 
procedures, the investigator must record this causal relationship in the source documents and 
CRF, as appropriate, and report such an assessment in accordance with the serious adverse 
event reporting requirements, if applicable. 
8.9. Exposure In Utero 
For investigational products within clinical trials, an Exposure In-Utero (EIU) occurs if: 
1. A female becomes, or is found to be, pregnant either while receiving or having 
been directly exposed to (eg, environmental exposure) the investigational product, 
or the female becomes, or is found to be, pregnant after discontinuing and/or 
being directly exposed to the investigational product (maternal exposure); 
2. A male has been exposed, either due to treatment or environmental, to the 
investigational product prior to or around the time of conception and/or is exposed 
during the partner pregnancy (paternal exposure). 
If any trial patient or trial patient’s partner becomes or is found to be pregnant while 
receiving the investigational product or within 6 months of the last treatment on study, the 
investigator must submit this information to sponsor on a Pregnancy Reporting Form.  In 
addition, the investigator must submit information regarding environmental exposure to the 
investigational product in a pregnant woman (eg a nurse reports that she is pregnant and has 
been exposed to a cytotoxic product by inhalation or spillage) using the Pregnancy Reporting 
Form.  This must be done irrespective of whether an adverse event has occurred and within 
24 hours of awareness of the pregnancy.  The information submitted should include the 
anticipated date of delivery (see below for information related to induced termination of 
pregnancy). 
Follow-up is conducted to obtain pregnancy outcome information on all pregnancy reports 
with an unknown outcome.  The investigator will follow the pregnancy until completion or 
until pregnancy termination (ie, induced abortion) and then notify sponsor of the outcome.  
The investigator will provide this information as a follow up to the initial Pregnancy 
Reporting Form.  The reason(s) for an induced abortion should be specified.  A pregnancy 


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report is not created when an ectopic pregnancy report is received since this pregnancy is not 
usually viable.  Rather, a serious adverse event case is created with the event of ectopic 
pregnancy. 
If the outcome of the pregnancy meets the criteria for immediate classification as a serious 
adverse event (ie, spontaneous abortion, stillbirth, neonatal death, or congenital anomaly 
[including that in an aborted fetus, stillbirth or neonatal death]), the investigator should 
follow the procedures for reporting serious adverse events. 
In the case of a live birth, the “normality” of the newborn can be assessed at the time of birth 
(ie, no minimum follow-up period of a presumably normal infant is required before a 
Pregnancy Reporting Form can be completed).  The “normality” of an aborted fetus can be 
assessed by gross visual inspection, unless pre-abortion test findings are suggestive of a 
congenital anomaly. 
Additional information about pregnancy outcomes that are classified as serious adverse 
events follows:  
• “Spontaneous abortion” includes miscarriage and missed abortion. 
• All neonatal deaths that occur within 1 month of birth should be reported, without 
regard to causality, as serious adverse events.  In addition, any infant death after 
1 month that the investigator assesses as possibly related to the in utero exposure to 
the investigational agent should be reported. 
8.10. Withdrawal Due to Adverse Events (See Also Patient Withdrawal) 
Withdrawal due to adverse event should be distinguished from withdrawal due to insufficient 
response, according to the definition of adverse event noted earlier, and recorded on the 
appropriate adverse event CRF page.   
When a patient withdraws due to a serious adverse event, the serious adverse event must be 
reported in accordance with the reporting requirements defined below. 
8.11. Eliciting Adverse Event Information 
The investigator is to report all directly observed adverse events and all adverse events 
spontaneously reported by the trial patient.  In addition, each trial patient will be questioned 
about adverse events in general. 
8.12. Reporting Requirements 
Each adverse event is to be assessed to determine if it meets the criteria for serious adverse 
event.  If a serious adverse event occurs, expedited reporting will follow local and 
international regulations, as appropriate. 


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Adverse events reporting, including suspected serious unexpected adverse reactions, will be 
carried out in accordance with applicable local regulations.  In this clinical trial, the reference 
document for determining whether an event is unexpected is the Investigator’s Brochure. 
All adverse events and serious adverse events will be reported via eCRF.  Adverse events 
should be reported using concise medical terminology in the AE page as well as in the SAE 
page of the eCRF. 
8.12.1. Serious Adverse Event Reporting Requirements 
If a serious adverse event occurs, Sponsor is to be notified via eCRF within 24 hours of 
awareness of the event by the investigator.  In particular, if the serious adverse event is fatal 
or life-threatening, notification to sponsor must be made immediately, irrespective of the 
extent of available adverse event information.  This timeframe also applies to additional new 
information (follow-up) on previously reported serious adverse event reports as well as to the 
initial and follow-up reporting of Exposure in Utero cases. 
In the rare event that the investigator does not become aware of the occurrence of a serious 
adverse event immediately (eg, if an outpatient trial patient initially seeks treatment 
elsewhere), the investigator is to report the event via eCRF within 24 hours after learning of 
it and document the time of his/her first awareness of the adverse event. 
For all serious adverse events, the investigator is obligated to pursue and provide information 
to sponsor in accordance with the timeframes for reporting specified above.  In addition, an 
investigator may be requested by sponsor to obtain specific additional follow-up information 
in an expedited fashion.  This information may be more detailed than that captured in the 
SAE page of eCRF.  In general, this will include a description of the adverse event in 
sufficient detail to allow for a complete medical assessment of the case and independent 
determination of possible causality.  Information on other possible causes of the event, such 
as concomitant medications and illnesses must be provided.  In the case of a patient death, a 
summary of available autopsy findings must be reported as soon as possible to sponsor or its 
designated representative.  
8.12.2. Non-Serious Adverse Event Reporting Requirements 
Non-serious adverse events are to be reported on the adverse event CRFs, which are to be 
submitted to sponsor. 
9. DATA ANALYSIS/STATISTICAL METHODS 
Two analysis populations will be defined: 
1. Intent-to-Treat Population: This population will include all patients who are 
randomized, with study drug assignment designated according to initial 
randomization, regardless of whether patients receive study drug or receive a different 
drug from that to which they were randomized.  This will be the primary population 
for evaluating all efficacy endpoints as well as patient characteristics.  


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2. As-Treated Population: The as-treated population consists of all patients who 
received at least 1 dose of study drug with treatment assignments designated 
according to actual study drug received.  This population will be the primary 
population for evaluating study drug administration/compliance and safety.  
9.1. Sample Size Determination  
The patient population in this study can be classified into 4 risk groups: 
a. 
pT2, pN0 or pNx, M0 and ECOG 0-1 
b. pT3, pN0 or pNx, M0 and ECOG 0-1 
c. 
pT4, pN0 or pNx, M0 and ECOG 0-1 
d. Any pT, pN1, M0 and ECOG 0-1 
Sample size was determined based on the analysis on the primary endpoint, DFS. 
The sample size for this study was calculated based on the following assumptions: 
• Time to DFS event follows an exponential distribution.  
• The percentage of patients randomized from the 4 risk groups, 2-year DFS rates for 
placebo arm and axitinib arm are assumed below 
Categories 
Risk groups 
Percentage of 
patients 
2-year DFS rate for 
placebo arm 
2-year DFS rate for 
axitinib arm 
1 
a. pT2/pN0 or pNX/M0 
b. pT3/pN0 or pNX/M0 
90% 
70% 
79% 
2 
c. pT4/pN0 or pNX/M0 
1% 
35% 
61% 
3 
d. Any pT/pN1/M0 
9% 
33% 
51% 
 
The assumptions of 2-year DFS rates for the placebo arm and axitinib arm are equivalent to 
the assumptions of hazard ratios to be 0.66, 0.47, and 0.61 for the 3 categories 1, 2 and 3 
respectively.  Given the assumed distribution of patients randomized (1:1) into each of these 
categories, the overall hazard ratio is estimated to be 0.654. 
Based on the above assumptions, a minimal number of 245 DFS events will be required to 
provide 90% power to detect the statistical difference in DFS with HR ≤ 0.654 between the 
two treatment groups with 2-sided significance level of 0.05. 
Applying a 1:1 randomization and a planned accrual period of 24 months, a maximum 
follow-up period of 60 months (5 years), and an assumed 23% drop-out rate by 18 months, it 
was estimated that approximately 700 patients will be enrolled. 
The final analysis will take place when approximately 245 DFS events are observed. 


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9.2. Efficacy Analysis 
9.2.1. Analysis of Primary Endpoint  
DFS based on the IRC review of tumor assessments (by imaging or histo-/cytopathology 
reports in the absence of IRC imaging confirmation) is the primary endpoint in this study.  
Factors (and levels in each factor) used in the stratified log-rank test will be stated in the 
SAP. 
The median DFS along with corresponding 95% CI will be estimated for each arm using 
Kaplan-Meier (KM) methods.  The hazard ratio (Arm A/Arm B) will be estimated by 
proportional Hazard regression stratified by the factors used in the stratified log-rank test, 
and with treatment in the model.  The DFS rates at 2 years and 5 years will also be estimated 
for each arm. 
The following sensitivity analyses will be performed for DFS: 
• DFS defined as in the primary analysis but based on local investigator assessment 
rather than IRC assessment.  The earlier of the tumor scan date and the date of 
collection of histo-/cytopathology specimen (where applicable) confirming recurrence 
or secondary malignancy will be used. 
• DFS based on IRC review defined as in the primary analysis but without censoring 
patients who receive further anti-tumor therapy or missed 2 or more consecutive 
tumor scans prior to recurrence or occurrence of a secondary malignancy or death.  In 
other words, patients receiving further anti-tumor therapy or missing 2 or more 
consecutive tumor scans before disease recurrence or occurrence of a secondary 
malignancy or death will be assigned with DFS events at the first date of recurrence 
or occurrence of a secondary malignancy or death.  In the absence of DFS event, DFS 
time will be censored at the date of last scan prior to the time of analyses.  Patients 
alive who do not have post baseline disease assessment will have their DFS times 
censored at randomization. 
• DFS based on IRC review defined as in the primary analysis but considering start of 
new anti-tumor therapy prior to recurrence, occurrence of secondary malignancy or 
death as events at the time of new anti-tumor therapy.   
• DFS based on IRC review as defined for the primary analysis but instead assigning 
the dates for events and censoring at the scheduled scan dates instead of the actual 
scan dates or the date of collection of histo-/cytopathology specimen.  Specifically, 
events that occur within +/- 4 weeks of a scheduled scan will be considered an event 
at the scheduled scan.  Events outside the 4 week window will be counted as events at 
the next scheduled scan time and censoring outside the 4 week window would be 
censored at the previous scheduled scan date. If, however, the event is death, the date 
of death will be used as the event date unless anti-tumor therapy was received prior to 
the date of death in which case the subject will be censored at the scheduled scan date 
prior to the date of anti-tumor therapy or for patients who miss 2 or more consecutive 


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tumor scans immediately followed by an event will be censored at the date of the last 
objective tumor assessment prior to the missing/not readable scans. 
• A parametric model utilizing techniques for interval-censored data will be used to 
compare the treatment effect.   
9.2.2. Analysis of Secondary Endpoints  
OS will be compared between Arm A and Arm B using a stratified log-rank test as described 
in the primary analysis for DFS.  The median OS along with corresponding 95% CI will be 
estimated by treatment arm using KM methods.  The hazard ratio (Arm A/Arm B) will be 
estimated by Proportional Hazard Regression stratified by the factors used in the stratified 
log-rank test and with treatment in the model.  
9.3. Analysis of Other Endpoints 
9.3.1. Patient Disposition 
The number of patients enrolled, treated, and evaluated for safety will be summarized.  In 
addition, the number of patients who completed the study and the number of patients who 
withdrew from the study and reasons for discontinuation will be summarized.  
9.3.2. Baseline Characteristics 
Demographic characteristics such as age, gender, height, weight, race, prior therapy, prior 
medication, physical examination, ECOG PS, signs and symptoms, and medical/oncology 
history will be tabulated. 
9.3.3. Study drug Administration/Compliance 
Study drug administration will be described in terms of the total number and median number 
of doses administered (ie, total dose), and reasons for the deviations from planned therapy. 
9.4. Safety Analysis 
Safety data will be summarized for all patients receiving at least one dose of study drug. 
9.4.1. Analysis of Adverse Events 
The serious adverse event reporting experience for this study begins from the time that the 
patient provides informed consent while the adverse event reporting experience for this study 
begins upon receiving the first dose of study drug and ends 28 days after the last dose of 
study drug is administered.  All AEs (serious and non-serious) reported from the first day of 
study treatment up to 28 days post study treatment will be considered treatment emergent 
AEs (TEAEs).   
Frequencies of patients experiencing at least one AE will be displayed by body system and 
preferred term according to MedDRA terminology.  Detailed information collected for each 
AE will include: A description of the event, duration, whether the AE was serious, intensity, 


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relationship to study drug, action taken, and clinical outcome.  Intensity (severity) of the AEs 
will be graded according to the CTCAE Version 4.0.  Emphasis in the analysis will be placed 
on AEs classified as treatment emergent. 
Summary tables will present the number of patients observed with TEAEs and corresponding 
percentages.  Within each table, the AEs will be categorized by MedDRA body system and 
preferred term.  Additional subcategories will be based on event intensity and relationship to 
study drug. 
Individual patient listings will be prepared for all AE data. 
9.4.2. Analysis of Clinical Laboratory Data 
Listing tables will be prepared for each laboratory measure and will be structured to permit 
review of the data per patient as they progress on treatment.   
Summary tables will be prepared to examine the distribution of laboratory measures over 
time.  Shift tables may be provided to examine the distribution of laboratory toxicities. 
9.4.3. Prior/Concomitant Medications and Non Drug Treatments/Procedures 
Prior medications, defined as those medications stopped prior to the first day of study 
treatment, and concomitant medications, defined as medications stopped, ongoing or started 
on or after the first day of study treatment up to 28 days post the last dose of study treatment, 
will be summarized, using the WHO-drug coding dictionary.  In addition, concomitant non 
drug treatments/procedures will be summarized using the MedDRA coding dictionary. 
9.4.4. Vital Sign and ECOG PS 
Descriptive statistics will be provided for ECOG PS at each assessment time.   
9.5. Interim Analysis  
A single interim analysis (IA) will be performed in the study.  O’Brien – Fleming type 
stopping boundaries based on the Lan-DeMets spending function will be applied.  Futility 
criteria are not used to calculate the nominal alphas (non-binding method) in order to control 
the overall Type I error. 
The interim analysis will take place after the first 184 events (75% of the events as assessed 
by the IRC) have occurred.  If the event occurrence pace is much slower than anticipated, the 
IA could be performed when less than 184 events observed (<75% of the total required) at 
sponsor’s discretion with the Data Monitoring Committee’s (DMC) consensus. 
The objectives of the interim analysis will be: 
1. To assess safety, including any unexpected toxicity.  If the results of the interim 
analysis indicate serious safety concerns, the Sponsor will consult with HRAs 
regarding stopping the clinical trial. 


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2. To allow for early stopping of the trial due to futility.  If the conditional power is low, 
the sponsor may choose to stop following up patients.  Conditional power 
calculations will be performed using SAS Version 9.2.  Criteria for futility will be 
provided in SAP. 
3. If the results of the interim analysis demonstrate statistically significant differences 
between the 2 treatment arms for DFS, the sponsor, in consultation with HRAs, will 
disseminate the results of the trial, and the interim analysis may be considered the 
final analysis for DFS.  The nominal level of significance for the interim analysis of 
DFS determined using the Lans-DeMets procedure with an O’Brien-Fleming type 
stopping rule will be 0.0194 (if the interim analysis is performed at 184 events). 
The following table summarizes the nominal significance level (2-sided) at each analysis 
when 75% and 100% of events are observed at the interim analysis and the final analysis. 
 
Fraction of total events 
Nominal α level 
75% 
0.0194 
100% 
0.0442 
 
The actual nominal α levels for the interim analysis and for the final analysis will depend on 
the fraction of total events occurred at the time of interim analysis. 
At the interim analysis statistical hypothesis tests will be performed only for the primary 
efficacy parameter, DFS (based on the IRC tumor assessments).  The stratified log-rank 
statistic will be calculated.  The DFS curve and OS curve estimated by the method of 
Kaplan-Meier will be summarized for each treatment group.  The interim safety report will 
review all aspects of the data collected for each patient.  Other important additional factors 
that reflect the integrity of the protocol will be addressed in the interim report. 
As per sponsor policy with respect to interim analyses of ongoing mortality studies, 
distribution of the analyses will be limited to appropriate individuals within the entire 
organization.  Results will be presented at the treatment group level only.  The results will 
not be shared with all the study team members or investigators nor broken down by center. 
9.6. Data Monitoring Committee  
A Data Monitoring Committee (DMC) will be formed to assure patient safety in this clinical 
trial.  The DMC will include a panel of experts recruited from outside of the institutions 
involved in this study.  The DMC will have access to unblinded patient treatment assignment 
information.  The DMC members will also have additional responsibility as they will be 
involved in the conduct and interpretation of data analyses for efficacy in addition to their 
primary responsibility for patient safety.  The committee will review tabulated aggregate 
toxicity and endpoint data.  The committee will submit written recommendations on the 
progress of the study to the Sponsor.  
Further procedural matters and meeting schedule will be defined by mutual agreement of 
DMC members in accordance with sponsor guidelines.  


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9.7. Independent Review Committee (IRC) 
The radiographic images and/or available local histo-/cytopathology reports (for patients who 
have site confirmation of recurrence or occurrence of secondary malignancy in the absence 
of IRC imaging confirmation) will be evaluated by an IRC to assess tumor status and to 
confirm recurrence or occurrence of a secondary malignancy.  The radiographic images 
and/or histo-/cytopathology reports documenting efficacy endpoints must be made available 
to allow the independent review.  The core laboratory will work with each clinical site to 
institute an acquisition protocol and other processes that will allow electronic transfer, where 
possible, of appropriate information used for tumor assessments.  Two independent reviewers 
will read scans.  Differences between the two independent reviewers should be resolved by a 
third reviewer (adjudicator) for final determination.  In addition, an independent clinical 
oncologist will assess available local histo-/cytopathology reports for evidence of malignancy 
for patients for which there is site confirmation of recurrence or occurrence of secondary 
malignancy in the absence of IRC imaging confirmation.  For primary statistical analysis, the 
results of the independent review will be used.   
10. QUALITY CONTROL AND QUALITY ASSURANCE 
During trial conduct, Sponsor or its agent will conduct periodic monitoring visits to ensure 
that the protocol and GCPs are being followed.  The monitors will review source documents 
to confirm that the data recorded on CRFs is accurate.  The investigator and institution will 
allow sponsor monitors or its agents and appropriate regulatory authorities direct access to 
source documents to perform this verification. 
The trial site may be subject to review by the Institutional Review Board (IRB)/Independent 
Ethics Committee (IEC), and/or to quality assurance audits performed by sponsor, and/or to 
inspection by appropriate regulatory authorities. 
It is important that the investigator(s) and their relevant personnel are available during the 
monitoring visits and possible audits or inspections and that sufficient time is devoted to the 
process.  
11. DATA HANDLING AND RECORD KEEPING 
11.1. Case Report Forms/Electronic Data Record 
A CRF is required and should be completed for each included patient.  The completed 
original CRFs are the sole property of sponsor and should not be made available in any form 
to third parties, except for authorized representatives of sponsor or appropriate regulatory 
authorities, without written permission from sponsor. 
It is the investigator's responsibility to ensure completion and to review and approve all 
CRFs.  CRFs must be signed by the investigator or by an authorized staff member.  These 
signatures serve to attest that the information contained on the CRFs is true.  At all times, the 
investigator has final personal responsibility for the accuracy and authenticity of all clinical 
and laboratory data entered on the CRFs.  Patient source documents are the investigator's 
patient records maintained at the trial site.  In most cases, the source documents will be the 


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hospital's or the investigator's chart.  In cases where the source documents are the hospital or 
the investigator's chart, the information collected on the CRFs must match those charts.  
In some cases, the CRF may also serve as the source document.  In these cases, Sponsor and 
the investigator must prospectively document which items will be recorded in the source 
documents and for which items the CRF will stand as the source document. 
11.2. Record Retention 
To enable evaluations and/or audits from regulatory authorities or sponsor, the investigator 
agrees to keep records, including the identity of all participating patients (sufficient 
information to link records, eg, CRFs and hospital records), all original signed ICD, copies of 
all CRFs, serious adverse event forms, source documents, and detailed records of treatment 
disposition.  The records should be retained by the investigator according to ICH, local 
regulations, or as specified in the Clinical Study Agreement, whichever is longer. 
If the investigator relocates, retires, or for any reason withdraws from the trial, Sponsor 
should be prospectively notified.  The trial records must be transferred to an acceptable 
designee, such as another investigator, another institution, or to sponsor.  The investigator 
must obtain sponsor's written permission before disposing of any records, even if retention 
requirements have been met. 
12. ETHICS 
12.1. Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
It is the responsibility of the investigator to have prospective approval of the trial protocol, 
protocol amendments, ICD, and other relevant documents, eg, advertisements, if applicable, 
from the IRB/IEC.  All correspondence with the IRB/IEC should be retained in the 
Investigator File.  Copies of IRB/IEC approvals should be forwarded to sponsor. 
The only circumstance in which an amendment may be initiated prior to IRB/IEC approval is 
where the change is necessary to eliminate apparent immediate hazards to the patients.  In 
that event, the investigator must notify the IRB/IEC and sponsor in writing within 5 working 
days after the implementation. 
12.2. Ethical Conduct of the Trial 
The trial will be performed in accordance with the protocol, International Conference on 
Harmonization Good Clinical Practice guidelines, and applicable local regulatory 
requirements and laws. 
12.3. Patient Information and Consent 
All parties will ensure protection of patient personal data and will not include patient names 
on any sponsor forms, reports, publications, or in any other disclosures.  In case of data 
transfer, Sponsor will maintain high standards of confidentiality and protection of patient 
personal data. 


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The ICD must be agreed to by sponsor and the IRB/IEC and must be in compliance with ICH 
GCP, local regulatory requirements, and legal requirements. 
The investigator must ensure that each trial patient, or his/her legally acceptable 
representative, is fully informed about the nature and objectives of the trial and possible risks 
associated with participation.  The investigator, or a person designated by the investigator, 
will obtain written ICD each patient or the patient's legally acceptable representative before 
any trial-specific activity is performed.  The ICD used in this trial, and any changes made 
during the course of the trial, must be prospectively approved by both the IRB/IEC and 
sponsor before use.  The investigator will retain the original of each patient's signed ICD. 
13. DEFINITION OF END OF TRIAL  
End of Trial in all participating countries is defined as collection of the final data point in the 
study.  Because this clinical trial includes a survival endpoint, the last data point is 
anticipated to be the last survival follow-up (ie, date last known alive or of death) prior to the 
cutoff date for database lock for the final Clinical Study Report.  
If the trial is terminated upon recommendation by the DMC according to prospectively-
defined criteria, End of Trial is defined as the date upon which sponsor received notification 
of the decision of the DMC. 
14. SPONSOR DISCONTINUATION CRITERIA 
Premature termination of this clinical trial may occur because of a regulatory authority 
decision, change in opinion of the IRB/IEC, drug safety problems, DMC, or at the discretion 
of sponsor.  In addition, Sponsor retains the right to discontinue development of axitinib, at 
any time. 
If a trial is prematurely terminated or discontinued, Sponsor will promptly notify the 
participating investigators.  After notification, the investigators must contact all participating 
patients within a week of notification.  As directed by sponsor, all trial materials must be 
collected and all CRFs completed to the greatest extent possible. 
15. PUBLICATION OF TRIAL RESULTS 
Sponsor supports the exercise of academic freedom and has no objection to publication by 
the principal investigator (PI) of the results of the study based on information collected or 
generated by the PI, whether or not the results are favorable to the Sponsor’s, and/or the 
Investigational product owner.  However, to ensure against inadvertent disclosure of 
confidential information or unprotected inventions, the investigator will provide Sponsor’s, 
and/or the Investigational product owner an opportunity to review any proposed publication 
or other type of disclosure of the results of the study (collectively, “publication”) before it is 
submitted or otherwise disclosed. 
The first publication is to be a joint publication covering all investigator sites, and that any 
subsequent publications by the PI will reference that primary publication.  However, if a joint 
manuscript has not been submitted for publication within 18 months of completion or 


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termination of the study at all participating sites, the investigator is free to publish separately, 
subject to the other requirements of this section. 
If there is any conflict between this protocol and the CSA, this protocol will control as to any 
issue regarding treatment of study patients, and the CSA will control as to all other issues. 
16. REFERENCES 
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7. Shraml P, Struckmann K, Hatz F, Sonnet S, Kully C, Gasser T, et al. VHL mutations and 
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23. Escudier B, Eisen T, Stadler WM, Szczylik C, Oudard S, Siebels M, et al. Sorafenib in 
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APPENDICES 
Appendix 1. Required Laboratory Tests 
Appendix 2. ECOG Performance Status 
Appendix 3. National Cancer Institute (NCI) Common Terminology Criteria for Adverse 
Events (CTCAE) 
Appendix 4. Nephrectomy Procedure  
Appendix 5. Abbreviations and Definitions of Terms 


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Appendix 1. Required Laboratory Tests 
 
Conventional 
Units 
Conversion 
Factor 
SI Units 
Hematology 
Hemoglobin (Hgb) 
g/dL 
x 10 
g/L 
Platelet count (Plt) 
103/mm3 
x 109 
10x12/L 
White blood count (WBC) 
103/mm3 
x 106 
109/L 
White blood cell differential 
Neutrophil 
% 
x 0.01 
fraction 
Lymphocytes 
% 
x 0.01 
fraction 
Chemistry 
Total bilirubin 
mg/dL 
x 17.1 
μmol/L 
Alanine transaminase (ALT) 
U/L 
N/A 
U/L 
Aspartate transaminase (AST) 
U/L 
N/A 
U/L 
Alkaline phosphatase 
U/L 
N/A 
U/L 
Lactic dehydrogenase (LDH) 
U/L 
x 0.016667 
μkat/L 
Albumin 
g/dL 
x 10 
g/L 
Total protein 
g/dL 
x 10 
g/L 
Sodium 
MEq/L 
x 1.0 
mmol/L 
Potassium 
MEq/L 
x 1.0 
mmol/L 
Chloride 
MEq/L 
x 1.0 
mmol/L 
Calcium 
mg/dL 
0.25 
mmol/L  
Phosphate 
mg/dL 
x 0.323 
mmol/L 
Blood urea nitrogen (BUN)/Urea 
mg/dL 
x 0.357 
mmol/L 
Creatinine 
mg/dL 
x 88.4 
μmol/L 
Glucose 
mg/dL 
x 0.055 
mmol/L 
PT/INR 
N/A 
N/A 
N/A 
Thyroid Function Tests 
 
 
 
Thyroid stimulating hormone (TSH) 
µU/mL 
x 1.0 
mIU/L 
Free T3 
pg/dL 
 
 
Free T4 
ng/dL 
 
 
Urinalysis 
 
 
 
Urine Protein 
N/A 
 
 


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Appendix 2. ECOG Performance Status 
Grade 
ECOG 
0 
Fully active, able to carry on all pre-disease activities without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, eg, light house work or office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work 
activities. Up and about more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours 
4 
Completely disabled.  Cannot carry on any self-care.  Totally confined to bed 
or chair 
5 
Dead 


AP311736 
Version - #10 Mar. 21, 2017 
 
CONFIDENTIAL 
Page 64 
Appendix 3. National Cancer Institute (NCI) Common Terminology Criteria for 
Adverse Events (CTCAE) 
The NCI CTCAE (Version 4.0) has been placed in the Study Reference Binder for this 
protocol.  Alternatively, the NCI CTCAE may be reviewed on-line at the following NCI 
website: 
http://ctep.cancer.gov/reporting/ctc.html 


AP311736 
Version - #10 Mar. 21, 2017 
 
CONFIDENTIAL 
Page 65 
Appendix 4. Nephrectomy Procedure 
Radical nephrectomy procedure performed either by open or by laparoscopic technique 
should include: early ligature of the renal vessels and en bloc removal of the intact specimen 
including tumoral kidney and surrounding perinephritic fat.  
Partial nephrectomy can be allowed provided all inclusion criteria are met and surgical 
margins are obtained.  
Adrenal gland removal should be performed in case of large upper pole tumor or in case of 
abnormal adrenal imaging on preoperative CT.  In other cases, routine adrenal gland excision 
is not mandatory and should be performed according to surgeon preferences.  
Lymph node dissection (LND) should be performed in case of suspicion of nodal invasion 
either on preoperative CT imaging or at intra-operative finding.  In other cases, LND will be 
performed according to surgeon preferences.  
In all cases, there must be no evidence of residual macroscopic disease on post-operative CT. 


AP311736 
Version - #10 Mar. 21, 2017 
 
CONFIDENTIAL 
Page 66 
Appendix 5.  Abbreviations and Definitions of Terms 
AE  
 
 
Adverse Event 
AIDS   
 
Acquired Immune Deficiency Syndrome 
AJCC  
 
American Joint Committee on Cancer 
ALT  
 
 
Alanine Transaminase 
AST  
 
 
Aspartate Transaminase 
ANC   
 
Absolute Neutrophil Count 
BP 
 
 
Blood Pressure 
BUN   
 
Blood Urea Nitrogen 
CI 
 
 
Confidence Interval 
CRF 
 
 
Case Report Form 
CSF 
 
 
Cerebral Spinal Fluid 
CT 
 
 
Computerized Tomography 
CTCAE  
 
Common Terminology Criteria for Adverse Events (US-NCI) 
CYP3A4/5 
 
Cytochrome P450 enzyme-3A4/5 
dBP 
 
 
diastolic Blood Pressure 
DFS 
 
 
Disease Free Survival 
DMC   
 
Data Monitoring Commitee 
ECG   
 
Electrocardiogram 
ECOG   
 
Eastern Collaborative Oncology Group 
EIU 
 
 
Exposure in Utero 
EQ-5D  
 
European Quality of Life Questionnaire in 5 functional domains 
GCP  
 
 
Good Clinical Practice 
Hgb 
 
 
Hemoglobin 
HIV  
 
 
Human Immunodeficiency Virus 
HRA 
 
 
Health Regulatory Authority 
ICD 
 
 
Informed Consent Document 
ICH 
 
 
International Conference Harmonisation  
IEC  
 
 
Independent Ethics Committee 
IFN-α  
 
Interferon-alfa 
IL-2  
 
 
Interleukin-2 
INR  
 
 
International Normalized Ratio 
IRB  
 
 
Institutional Review Board 
IRC 
 
 
Independent Review Commitee 
IUD 
 
 
Intrauterine Device 
KM 
 
 
Kaplan Meyer 
LDH   
 
Lactic Dehydrogenase 
LND 
 
 
Lymph Node Dissection 
MedDRA  
 
Medical Dictionary for Regulatory Activities 
mRCC  
 
Metastatic Renal Carcinoma  
MRI  
 
 
Magnetic Resonance Imaging 
NCI  
 
 
National Cancer Institute 
ORR 
 
 
Objective response rate 
OS  
 
 
Overall Survival 
PFS 
 
 
Progression Free Survival 
PLT 
 
 
Platelet  
PRO 
  
 
Patient Reported Outcomes 
PT  
 
 
Prothrombin Time 
QTc 
 
 
Corrected Q-T interval 
RCC   
 
Renal Cell Carcinoma 


AP311736 
Version - #10 Mar. 21, 2017 
 
CONFIDENTIAL 
Page 67 
sBP 
 
 
systolic Brood Pressure 
TEAE  
 
Treatment Emergent Adverse Event 
TNM  
 
Tumor, Nodes, Metastases 
TX 
 
 
Treatment 
TSH 
 
 
Thyroid Stimulating Hormone 
ULN   
 
Upper Limit of Normal 
UPC 
 
 
urine protein: urine creatinine ratio 
VEGF   
 
Vascular Endothelial Growth Factor 
WBC   
 
White Blood Cell 
 


Title: Protocol Approval Template 
Document No.: TMP-302-1  
Version No.: 1.0 
 
 
SFJ Pharmaceuticals, Inc.® 
Proprietary and Confidential 
Page 1 of 1 
 
 
 
 
 
 
PROTOCOL APPROVAL SIGNATURE PAGE 
Compound: 
AG-013736 
Compound Name: 
Axitinib 
Protocol Number: 
AP311736 
Phase: 
III 
Version and Date 
version - 10    March 21, 2017 
 
 
 
 
 
Rolf Linke 
Chief Medical Officer 
SFJ Pharmaceuticals 
 
 
                                                                               
 
 
 
               
________________________________________________________________________ 
Rolf Linke 
 
 
 
 
 
 
Date   
 
 
 
21. March 2017

SAP_000.pdf: 
 
Statistical Analysis Plan  
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STATISTICAL ANALYSIS PLAN 
 
 
Adjuvant Axitinib Treatment of Renal Cancer: A 
Randomized Double-blind Phase 3 Study of Adjuvant 
Axitinib vs. Placebo in Subjects at High Risk of Recurrent 
RCC 
 
Study No. AP311736 
 
 
 
 
 
 
 
 
 
 
 
 
 


06. March 2018


 
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Table of Contents 
 
Modification History ...................................................................................................... 5 
List of Abbreviations and Definition of Terms .......................................................... 11 
1. 
Introduction ........................................................................................................ 13 
2. 
Study Objectives ................................................................................................. 13 
2.1. 
Primary Objective ............................................................................................... 13 
2.2. 
Secondary Objectives ......................................................................................... 13 
3. 
Study Design ....................................................................................................... 13 
3.1. 
General Description ............................................................................................ 13 
3.2. 
Treatments .......................................................................................................... 14 
3.2.1. 
Treatments Administered .................................................................................... 14 
3.2.2. 
Method of Assigning Subjects to Treatment Groups .......................................... 15 
3.2.3. 
Blinding ................................................................................................................ 17 
3.3. 
Determination of Sample Size ............................................................................ 17 
3.4. 
Changes in the Conduct of the Study or Planned Analyses ................................ 18 
3.4.1. 
Changes in the Conduct of the Study .................................................................. 18 
3.4.2. 
Changes from Analyses Planned in the Protocol ................................................ 19 
4. 
Analysis Populations .......................................................................................... 20 
4.1. 
Intent-To-Treat Population ................................................................................. 20 
4.2. 
As-Treated Population ........................................................................................ 20 
4.3. 
Treatment Misallocations ................................................................................... 20 
4.4. 
Protocol Deviations ............................................................................................ 20 
5. 
Efficacy Endpoints and Covariates .................................................................. 21 
5.1. 
Primary Efficacy Endpoint ................................................................................. 21 
5.2. 
Secondary Efficacy Endpoint ............................................................................. 22 
5.3. 
Safety Endpoints ................................................................................................. 22 
5.4. 
Covariates ........................................................................................................... 23 
5.4.1. 
Stratification Factors ............................................................................................ 23 
6. 
Statistical Methods ............................................................................................. 23 
6.1. 
General Methodology ......................................................................................... 23 
6.1.1. 
Analyses for Continuous Data ............................................................................. 24 
6.1.2. 
Analyses for Categorical Data ............................................................................. 24 
6.1.3. 
Analysis of Time-To-Event Endpoints ............................................................... 24 
6.2. 
Handling of Dropouts or Missing Data ............................................................... 24 
6.2.1. 
Missing Data in Adverse Event Dates ................................................................. 25 


 
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6.2.2. 
Missing Data in Safety Endpoints ....................................................................... 25 
6.3. 
Interim Analysis and Data Monitoring Check spending function ...................... 25 
6.4. 
Multicenter Studies ............................................................................................. 27 
6.5. 
Multiple Comparisons/Multiplicity .................................................................... 28 
7. 
Statistical Analysis ............................................................................................. 28 
7.1. 
Analysis of Primary Efficacy Endpoint .............................................................. 28 
7.1.1. 
Disease-Free Survival Based on IRC Review ..................................................... 28 
7.1.2. 
Methods for Evaluating the Validity of Model Assumptions ............................. 28 
7.2. 
Analysis of Secondary Efficacy Endpoint .......................................................... 29 
7.2.1. 
Overall Survival  (OS) ......................................................................................... 29 
7.3. 
Additional Analyses of Efficacy ......................................................................... 30 
7.3.1. 
Sensitivity Analyses ............................................................................................. 30 
7.3.2. 
Subgroup Analyses .............................................................................................. 32 
7.3.3. 
Post hoc Analyses ................................................................................................ 33 
7.3.4. 
Exploratory Analyses ........................................................................................... 33 
7.4. 
Standard Analyses .............................................................................................. 33 
7.4.1. 
Disposition of Subjects ........................................................................................ 33 
7.4.2. 
Demographic and Other Baseline Characteristics .............................................. 34 
7.4.3. 
Extent of Exposure .............................................................................................. 34 
7.5. 
Analysis of Safety ............................................................................................... 35 
7.5.1. 
Adverse Events .................................................................................................... 36 
7.5.2. 
Clinical Laboratory Evaluation ........................................................................... 38 
7.5.3. 
ECG Evaluations .................................................................................................. 40 
7.5.4. 
Vital Signs,  Physical Findings, and Other Observations Related to Safety ...... 40 
7.5.5. 
Prior/Concomitant Medications........................................................................... 41 
8. 
References ........................................................................................................... 41 
9. 
Appendix A ......................................................................................................... 43 
10. 
Appendix B ......................................................................................................... 50 
11. 
Table Shells and Specifications ......................................................................... 52 
11.1. 
Table Shells ........................................................................................................ 52 
12. 
Figure Shells and Specifications ....................................................................... 52 
12.1. 
Figure Shells ....................................................................................................... 52 
13. 
Listing Shells and Specifications ....................................................................... 52 
13.1. 
Listing Shells ...................................................................................................... 52 
14. 
Programming Conventions for Outputs: ......................................................... 52 
 


 
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Modification History 
 
Unique 
Identifier 
for this 
Version 
Date of the 
Document 
Version 
Author 
Significant Changes from  
Previous Authorized Version 
Draft 1.0 
05DEC2011 
Mark Shaw 
N/A – First Version 
Draft 1.1 
10JAN2012 
Mark Shaw 
Updates based on customer 
comments and updated version of 
the protocol (Version 3) 
Draft 2.0 
11JAN2012 
Mark Shaw 
Updates following Senior 
Biostatistical Review of Version 1.1 
Final 1.0 
23JAN2012 
Mark Shaw 
Updates based on customer 
comments on Draft V2.0 
Final 2.0 
27JAN2012 
Mark Shaw 
Update to definition of Signs and 
Symptoms in Section 8.4 
Final 3.0 
01MAR2012 
Mark Shaw 
Updates following customer 
proposals 
Final 4.0 
16JUL2012 
Mark Shaw 
Updates based on Version 4 of the 
protocol 
Final 5.0 
31JAN2013 
Mark Shaw 
Addition of sensitivity analyses 
based on SFDA comments. 
Updates based on Version 6 of the 
protocol. 
Update to stratification defined in 
Section 7.2. 
Final 6.0 
02SEP2013 
Caroline 
O’Brien 
Updated based on Version 7 of the 
protocol. 
Draft 7.0 
23APR2014 
Denise 
Williamson 
Updated based on Version 8 of the 
protocol. 
Draft 8.0 
05MAR2015 
Troy Johnson 
Updated based on Version 9 of the 
protocol. 


 
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Draft 9.0 
04JUN2015 
Troy Johnson 
Feedback from reviewers 
incorporated 
Draft 10.0 
22NOV2016 
Lynya Engel 
Addition of sensitivity analysis 
including histologically confirmed 
subjects. 
 
Addition of sensitivity analysis of 
overall survival censoring unblinded 
subjects at the date of unblinding. 
 
Addition of risk group analyses. 
 
Renamed subset analyses of all 
efficacy and safety by country to 
“Post hoc analyses.” 
Draft 11.0 
JAN2017 
Lynya Engel 
Changed SAP template. 
 
Added Treatment Misallocations 
section. 
 
Added section for testing model 
assumptions. 
 
Added possible exploratory 
endpoints including RMST. 
 
Added censoring rule tables as 
Appendix A. 
 
Draft 12.0 
FEB2017 
Lynya Engel 
Added futility analysis 
 
Added removing a stratification 
factor in the analysis of the primary 
endpoint if the model does not 


 
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converge 
 
Clarified units of measurement for 
DFS and OS analyses 
 
Added new censoring rule to 
include censoring subjects who had 
two or more missed visits  
 
Added specification to DFS 
sensitivity analyses regarding if 
analyses would be based on IRC 
Review or Investigator Assessments 
 
Added more details to DFS 
sensitivity analysis using scheduled 
visits 
 
Added more details regarding 
interval censoring used in 
parametric model 
 
Removed DFS analyses stratified by 
risk group only 
 
Removed DFS analyses stratified by 
country only 
 
Removed DFS analysis by years of 
treatment  
 
Changed model for subgroup 
analyses to not include  
stratification factors 
 


 
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Changed what had previously been 
defined as “subgroup” to “risk 
group” 
 
Removed Overall Survival 
sensitivity analyses 
 
Modified summaries of dose 
interruptions, dose reductions and 
dose increases 
 
Added guidelines for imputing dates 
for adverse events 
 
Added section on missing data in 
safety endpoints 
 
Defined Day 1 for laboratory 
analyses and expanded details for 
worst category summarizations 
Draft 13.0 
FEB2017 
Lynya Engel 
 Added details for how to calculate 
discordance rates 
 
Methods for evaluating the validity 
of model assumptions for overall 
survival were removed 
 
Added clarity for how baseline will 
be defined for laboratory values 
 
Removed shift tables demonstrating 
frequencies of ECOG increases of  
≥ +1 and +2 change from baseline 
to worst value after first dose  
 
Removed summaries of subjects 


 
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with a Worst-Grade of >=Grade 4 
TEAE and summaries of subjects 
with a Worst-Grade of >=Grade 4 
related TEAE 
 
Removed summaries of subjects 
with a Grade 5 TEAE through 28 
days of last dose of the study 
treatment judged not to be causally 
related to PD 
 
Removed summaries of subjects 
with a Grade 5 TEAE > 28 days 
after last dose of the study treatment 
not judged to be causally related to 
PD 
 
Added details for start date of anti-
tumor treatments during follow-up 
Draft 13.1 
MAR2017 
Lynya Engel 
Updated name of Sponsor 
Representative 
Draft 14.0 
APR2017 
Lynya Engel 
Updated based on Version 10 of the 
protocol 
 
Updated list of abbreviations 
 
Added analysis of relative dose 
 
Deleted treatment compliance 
analyses 
 
Added exploratory landmark 
analysis 
 
Revised Appendix A  


 
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Added Appendix B 
Draft 15.0 
APR2017 
Lynya Engel 
Updates based on customer 
comments 
Final 7.0 
APR2017 
Lynya Engel 
Updates based on customer 
comments 
Final 8.0 
(draft v1.0) 
DEC2017 
Lynya Engel 
Updates based on customer 
comments 
Final 8.0 
(draft v2.0) 
FEB2018 
Lynya Engel 
Added clarification to censoring 
rules and stopping criteria. 


 
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List of Abbreviations and Definition of Terms 
 
 
 
AE 
Adverse Event 
AJCC 
American Joint Committee on Cancer 
ALT 
Alanine Aminotransferase 
ANC 
Absolute Neutrophil Count
AST 
Aspartate Aminotransferase
AT 
As-Treated 
ATC 
Anatomical Therapeutic Chemical 
BID 
Twice a day
BMI 
Body Mass Index
BP 
Blood Pressure 
BUN 
Blood Urea Nitrogen 
CI 
Confidence Interval 
CRF 
Case Report Form
CT 
Computed Tomography
CTCAE 
Common Terminology Criteria for Adverse Event 
DBP 
Diastolic Blood Pressure 
DFS 
Disease-Free Survival
DMC 
Data Monitoring Committee
EDR 
Early Discrepancy Rate 
ECG 
Electrocardiogram 
ECOG PS 
Eastern Collaborative Oncology Group Performance Status 
HLGT 
High Level Group Term
HLT 
High Level Term 
HR 
Hazard Ratio 
HRAs 
Health Regulatory Authorities 
IA 
Interim Analysis
ICH 
International Conference on Harmonisation
INR 
International Normalizing Ratio 
INV 
Investigator Assessment 
IRC 
Independent Review Committee 
IVRS 
Interactive Voice Response System
IWRS 
Interactive Web Response System 
LDH 
Lactate Dehydrogenase 
LDR 
Late Discrepancy Rate 
MedDRA 
Medical Dictionary for Regulatory Authority
MG 
Milligrams
MRI 
Magnetic Resonance Imaging 


 
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MS 
Millimeters/Second
NCI 
National Cancer Institute 
NLR 
Neutrophil to Lymphocyte Ratio 
OS 
Overall Survival 
PH 
Proportional Hazards
PI 
Principal Investigator 
PS 
Performance Status 
PT 
Preferred Term 
QTcB 
QT interval corrected for heart rate using Bazett’s method 
QTcF 
QT interval corrected for heart rate using Fridericia’s 
method 
RCC 
Renal Cell Carcinoma
SAE 
Serious Adverse Event
SAP 
Statistical Analysis Plan 
SBP 
Systolic Blood Pressure 
SMQ 
Standardised MedDRA Query 
SOC 
System Organ Class
StD 
Standard Deviation
TEAE 
Treatment Emergent Adverse Event 
TSH 
Thyroid Stimulating Hormone 
ULN 
Upper Limit of Normal 
UPC 
Urine Protein to Creatinine
WBC 
White Blood Cell 
WHO 
World Health Organization 
YR 
Year 
 


 
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1. 
Introduction 
 
This document describes the rules and conventions to be used in the presentation and analysis of 
efficacy and safety data for protocol AP311736. It describes, in detail, the data to be summarized 
and analyzed, including specifics of the statistical analyses to be performed.  
 
This statistical analysis plan is based on the final Protocol version 101, dated 21March 2017.  
This document may modify the plans outlined in the protocol and supersedes the protocol;  
however, any major modifications of the primary endpoint or its analyses will be reflected in a 
protocol amendment. 
 
Any deviations from this analysis plan will be described in the Clinical Study Report. 
 
2. 
Study Objectives 
 
 
2.1. 
Primary Objective 
 
To demonstrate an improvement in disease free survival (DFS) in subjects at high risk of 
recurrent renal cell carcinoma (RCC) randomly assigned to adjuvant axitinib vs. placebo 
after nephrectomy. 
 
2.2. 
Secondary Objectives 
 
• 
Compare overall survival (OS) associated with axitinib to that associated with placebo; 
• 
Assess safety/toxicity profile of administration of axitinib 
 
3. 
Study Design 
 
 
3.1. 
General Description 
 
This is a prospective, randomized, double-blind placebo controlled Phase 3 trial of oral axitinib 
starting at 5 mg twice daily vs. placebo given for up to 3 years, with a minimum of 1 year, in 
subjects at high risk of recurrent RCC aged 18 or over (20 or over in Japan, Korea and Taiwan). 
The dose may be increased or decreased depending on individual subject tolerance of axitinib. 
 
Approximately 700 subjects will be randomized in a 1:1 ratio between axitinib vs placebo.  
Subjects should begin study treatment within 7 days after randomization.  Randomization will 
occur no sooner than 4 weeks post nephrectomy and no later than 12 weeks post nephrectomy. 
 
Recurrence or occurrence of a secondary malignancy will be followed up at clinic visits until the 
time of the final analysis (regardless of the duration of treatment) every 16 weeks for the first 3 
years from initiation of study treatment (also, at the end of treatment) and every 6 months 


 
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thereafter for the remainder of the follow-up period.  The total duration of the study from first 
subject in to final analysis is estimated to be 5 years. 
 
All subjects will be followed for OS status (regardless of the duration of treatment) every 16 
weeks until the time of final DFS analysis.  Survival status can be ascertained by telephone 
contact. At the time of final DFS analysis, OS results will be analyzed and summarized. 
 
A single interim analysis (IA) of efficacy and safety will be performed after approximately 184 
DFS events (approximately 75% of the total number of required events as 
assessed by the independent review committee [IRC]) have occurred.  If the event occurrence 
pace is much slower than anticipated, the IA could be performed when less than 184 events are 
observed (<75% of the total required) at the sponsor’s discretion with the Data Monitoring 
Committee’s (DMC) consensus. To protect the integrity of the study and to preserve the Type 1 
error, a fraction of alpha will be spent at the interim analysis of  DFS based on an O’Brien-
Fleming spending function.  The stopping boundaries will be calculated based on the actual 
number of events at the time of the interim analysis. 
 
The objectives of the interim analysis will be: 
 
• 
To assess the safety, including any unexpected toxicity. 
• 
To allow for early stopping of the trial due to futility. 
• 
To assess the efficacy of the study drug to allow stopping of trial for success of efficacy. 
 
3.2. 
Treatments 
 
3.2.1. 
Treatments Administered 
 
Subjects will receive axitinib (at a starting dose of 5 mg twice a day [BID]) or placebo, identical 
in appearance to the active study drug, BID. Both should be taken orally with or without food. 
 
Dose adjustments, including dose increase or dose reduction will be based on adverse events 
(AEs) experienced by the individual subject.  Study drug will be taken beginning on Day 1 of the 
study.  Doses should be taken approximately 12 hours apart for continuous dosing.  Subjects 
should be instructed to take their doses at approximately the same times each day.  If a subject 
vomits or misses a dose, an additional dose should not be taken. The next prescribed dose should 
be taken at the usual time. Missed or vomited doses, must be indicated in the source documents 
and case report forms (CRFs). Study treatment will be administered in cycles of 4 weeks in 
duration. 
 
Subjects who tolerate axitinib or placebo with no AEs related to study drug above Common 
Terminology for Adverse Events (CTCAE) Grade 2 for a consecutive 2-week period may have 
their dose increased by one dose level to maximum of 10 mg BID as per Table 1 (unless the 
subject’s blood pressure [BP] is >150/90 mm Hg or the subject is receiving antihypertensive 
medication).  The clinical judgment of the treating physician should be exercised in titrating the 


 
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axitinib/placebo dose. 
 
Subjects experiencing adverse drug reaction should undergo dose modification as recommended 
in Section 5.3.4 of the protocol. 
 
Once the dosage is reduced, it can be uptitrated again. 
 
Concomitant medications that are known to substantially inhibit the enzyme, CYP3A4/5, should 
be avoided as much as medically possible on this study as in Section 5.5.1 of the protocol. If a 
strong CYP33A4/5 inhibitor must be co-administered, based on investigator judgment, the dose 
of study drug (axitinib/placebo) should be decreased by one or more dose levels. 
 
 
Table 1 Available Axitinib/Placebo Dose Levels 
Dose Level 
Dose
Dispensed As
+2 
10 
mg 
BID
2 X 5 mg Tablets BID  
+1 
7 mg 
BID
1 X 5 mg Tablet  BID + 2 X 1mg Tablets 
BID
0 (Starting 
Dose) 
5 mg 
BID 
1 X 5 mg Tablet BID (twice daily) 
-1 
3 mg 
BID
3 X 1 mg Tablets BID     
-2 
2 mg 
BID
2 X 1 mg Tablets BID     
-3 
1 mg 
BID
1 X 1 mg Tablet BID 
     
 
3.2.2. 
Method of Assigning Subjects to Treatment Groups 
 
Subjects must be randomized no earlier than 4 weeks and no later than 12 weeks after 
nephrectomy and treatment should be started within 7 days after randomization.  Subject 
eligibility must be confirmed by IRC assessment of imaging by a sponsor designated center prior 
to randomization. 
 
Subjects must be randomized based on the assessment by the IRC when there is a discrepancy 
between the local and the IRC imaging review. 
 
A centralized system will be used to assign Subject numbers and randomize subjects to blinded 
study drug: axitinib, or blinded placebo identical in appearance to the active study drug. 
 
After a subject has provided written informed consent and has completed the necessary 
screening assessments, the clinical site must contact a centralized internet/telephone registration 
system (IWRS/IVRS), to enroll the subject into study.  
 


 
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At the time of registration, the clinical site staff must provide site and subject identifiers and 
demographic information.  The registration system will assign a unique subject identification 
number.  The system will also be used to assign blinded study medication bottles.  Subjects will 
be randomized to one of two arms: 
 
Axitinib 5 mg BID taken orally or Placebo tablets BID taken orally and will be stratified by; 
 
1. Risk group*  
a.   pT2, pN0 or pNx, M0 and ECOG PS 0-1  
b. pT3, pN0 or pNx, M0 and ECOG PS 0-1  
 
c. 
pT4, pN0 or pNx, M0 and ECOG PS 0-1 
d. Any pT, pN1, M0 and ECOG PS 0-1 
 
* Risk Groups are based on American Joint Committee on Cancer (AJCC) TNM staging version 
2010 and Eastern Collaborative Oncology Group (ECOG) performance status (PS) 
2. Country (note only those subjects in risk group a or b will be stratified by country) 
a. 
Japan 
b. China (Mainland) 
c. 
Korea 
d. Taiwan 
e. 
Hong Kong 
f. 
India 
g. USA 
h. France 
i. 
Spain 
 
Eligible subjects will be initially randomized in a 1:1 ratio to one of the two treatments using the 
registration system. 
 
Randomization shall continue until a minimum of 10% of subjects are represented in this study 
from risk group c and d.  Based on amendment 8 of the protocol, risk group a was closed to 


 
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further enrollment, to keep the number of subjects in risk group b, c, and d to about 90% or 
more. 
 
 
3.2.3. 
Blinding 
 
The study is double-blind.  Axitinib will be supplied as 1 mg and 5 mg film-coated tablets for 
oral administration in light-protecting bottles.  Placebo will match all dose formulations and will 
be identical in appearance to the active study drug. 
 
At the initiation of the trial, the trial site will be instructed on the method for breaking the blind. 
The method will be an electronic process.  Blinding codes should only be broken in emergency 
situations for reasons of subject safety, or if the subject has a confirmed recurrence or occurrence 
of a secondary malignancy with limited alternative treatment option and knowledge of study 
drug is required to facilitate further treatment decisions. For those with suspected recurrence, the 
site must await results from the IRC. The decision to break the blind must be approved by the 
Sponsor prior to doing so. When the blinding code is broken, the reason must be fully 
documented in the site source document. In these instances, only the principal investigator (PI) is 
unblinded.  The broader study team will remain blinded. 
 
Where unblinded study data is to be produced for review by the DMC for the study, a 
biostatistics team in a separate location from the study team will be used to produce and 
distribute the unblinded data.  The data will only be distributed to unblinded personnel as agreed 
in a separate DMC analysis plan and/or DMC charter. 
 
3.3. 
Determination of Sample Size 
 
The subject population in this study can be classified into 4 risk groups, as defined in section 
3.2.2. 
Sample size was determined based on the analysis on the primary endpoint, DFS. 
The sample size for this study was calculated based on the following assumptions: 
• 
Time to DFS event follows an exponential distribution.  
• 
The percentage of subjects randomized from the 4 risk groups, 2-year DFS rates for 
placebo arm and axitinib arm are assumed below: 
      Table 2 
DFS Rates Per Risk Group 
Categories 
Risk groups 
Percentage 
of subjects
2-year DFS rate 
for placebo arm 
2-year DFS rate 
for axitinib arm
1 
a. pT2/pN0 or pNX/M0
b. pT3/pN0 or pNX/M0
90% 
70% 
79% 
2 
c. pT4/pN0 or pNX/M0
1%
35%
61% 
3 
d. Any pT/pN1/M0
9%
33%
51% 


 
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The assumptions of 2-year DFS rates for the placebo arm and axitinib arm are equivalent to the 
assumptions of hazard ratios to be 0.66, 0.47, and 0.61 for the 3 categories 1, 2 and 3 
respectively.  Given the assumed distribution of subjects randomized (1:1) into each of these 
categories, the overall hazard ratio is estimated to be 0.654. 
Based on the above assumptions, a minimal number of 245 DFS events will be required to 
provide 90% power to detect a hazard ratio (HR) of 0.654 between the two treatment groups with 
2-sided significance level of 0.05. The nominal significance level assuming a single interim (at 
75% of the required events) and a final analysis for efficacy will be determined by using the Lan-
DeMets procedure with an O’Brien-Fleming stopping rule.  At the final analysis, an observed 
HR ≤0.773 would be required for statistical significance with the overall Type I error rate 
preserved at the nominal 0.05 level. 
Applying a 1:1 randomization and a planned accrual period of 24 months, a maximum study  
period of 60 months (5 years), it was estimated that approximately 700 subjects will be required. 
This assumes a 23% drop-out rate by 18 months. 
The final analysis will take place when approximately 245 DFS events are observed. 
 
3.4. 
Changes in the Conduct of the Study or Planned Analyses 
A summary of the key amendments that occurred between November 2011 and March 2017 with 
an impact on the conduct of the study and planned analyses are described below. 
 
 
 
3.4.1. 
Changes in the Conduct of the Study 
Amendment#6 (Jan 2013): (a) inclusion criteria was modified and sample size determination 
had been adjusted to include any Furhrman grade and the subject population was classified into 4 
risk groups: (1) pT2, pN0 or pNx, M0 and ECOG PS 0-1; (2) pT3, pN0 or pNx, M0 and ECOG 
PS 0-1(3) pT4, pN0 or pNx, M0 and ECOG PS 0-1 (4) Any pT, pN1, M0 and ECOG PS 0-1. 
 
Amendment#7 (Aug 2013) A change was made that all subjects would be followed up for OS 
status every 16 weeks until the time for final DFS analysis rather than until the time for analysis 
of OS. Instructions were added that tumor imaging should be obtained if they were not performed 
within 8 weeks of the end of study or at withdrawal for subjects who discontinue treatment for 
reasons other than disease progression. A modification was made that randomization would 
continue until a minimum of 10% of subjects are represented in the study from risk groups c and 
d. Other modifications included allowing unscheduled assessments to occur coincident with 
safety events, early discontinuation of study treatment, early study termination, suspected 
recurrence or suspected occurrence of a secondary malignancy between protocol specified study 
visits. Instructions were added that for subjects who present with findings suggestive of a tumor 
recurrence or secondary malignancy, histopathological confirmation of the diagnosis should be 
obtained except in subjects whose lesions are deemed by the investigator not to be amenable to 


 
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biopsy. For these subjects, recurrent disease would be documented using Magnetic Resonance 
Imaging (MRI) or Computed Tomography (CT) if MRI is not available or is contraindicated. In 
addition, a modification was made that all histopathologically confirmed secondary malignancy 
must be reported as a Serious Adverse Event (SAE). 
 
Amendment#8 (Feb 2014) (a) Inclusion criteria was modified to increase the number of subjects  
with higher risk of RCC recurrence: subjects with pT2, pN0 or pNx, M0 and ECOG PS 0-1 were 
excluded from enrollment in the trial. (b) Assuming a 23% drop-out rate, the sample size has 
been adjusted from 592 subjects to 692 enrolled subjects to account for the drop-out. 
 
 
3.4.2. 
Changes from Analyses Planned in the Protocol 
Amendment#6 (Jan 2013): - New sensitivity analyses were added to analysis of primary 
endpoint of DFS as described in Section 7.3.1. 
Amendment#9 (Oct 2014)- The interim analysis plan was changed from two initial planned 
interim analyses (one at 47 events or 20% of the events as assessed by IRC and one at 142 
events) to one interim analysis that will take place at 184 events (75% of events as assessed by 
IRC). To protect the integrity of the study and to preserve the Type 1 error, a fraction of alpha 
will be spent at the interim analysis based on an O’Brien Fleming spending function. The 
objectives of the new planned interim analysis will be: (a) to assess the safety, including any 
unexpected toxicity; (b) to allow for early stopping of the trial due to futility; (c) to assess the 
efficacy of the study drug to allow stopping of trial for success of efficacy. 
 
Amendment#10 (Mar 2017): The primary endpoint was modified to include evaluations of 
available local histo-/cytopathology reports by an independent IRC oncologist for cases in which 
recurrence or occurrence of secondary malignancy had been confirmed by the site in the absence 
of IRC imaging confirmation. Specifically, the date of recurrence or the occurrence of secondary 
malignancy will be defined as the date of the tumor scan or the date of collection of the histo-
cytopathological specimen (for subjects who have site confirmed recurrence or occurrence of 
secondary malignancy in the absence of IRC imaging confirmation) that demonstrated 
unequivocal recurrence or secondary malignancy according to protocol criteria. If both imaging 
and histo-/cytopathological confirmation of recurrence or secondary malignancy are available, 
the earlier of the two dates will be considered. In addition, the protocol was amended to include 
censoring subjects who have two or more consecutively missed or not readable scans 
immediately prior to an event. The date of censoring in these instances will be on the date of the 
most recent scan prior to the missing/not readable scans. The protocol was further amended to 
remove excluding as an event the occurrence of a second primary cancer that was basal cell 
carcinoma, squamous cell skin cancer or in situ carcinoma of the cervix uteri. Additionally, the 
protocol was also changed to record anti-tumor therapy even after 28 days after last treatment. 
More details were provided for analysis of DFS defined by assigning dates for events and 
censoring at scheduled scan dates.  


 
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4. 
Analysis Populations 
 
Screen failure subjects will not be included in any analyses. 
 
Subjects who start any of the study drugs (i.e., axitinib or placebo) will be considered to have 
started treatment.  
 
4.1. 
Intent-To-Treat Population 
 
Intent-to-Treat (ITT) Population: This population will include all randomized subjects regardless 
of whether or not treatment was administered and will be based on randomized treatment 
assignment.  This population will be the primary population for evaluating baseline 
characteristics and efficacy. 
 
4.2. 
 As-Treated Population 
 
As-Treated (AT) Population: The As-Treated population consists of all subjects who received at 
least 1 dose of study medication with treatment assignments designated according to actual study 
treatment received.  This population will be the primary population for evaluating treatment 
administration/compliance and safety.    
 
 
 
The number and percentage of subjects in each population will be summarized by treatment 
group and listed. 
 
 
4.3. 
Treatment Misallocations 
 
If subjects were: 
• 
Randomized but not treated, then they will be reported under their randomized 
treatment group for efficacy analyses.  However, they are by definition 
excluded from the safety analyses as actual treatment is missing. 
 
 
• 
Randomized but took incorrect treatment, then they will be reported under 
their randomized treatment group for all efficacy analyses, but will be reported 
under the treatment they actually received for all safety analyses. 
 
A summary table of treatment misallocations will be provided. 
 
4.4. 
Protocol Deviations 
 


 
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Subjects with major protocol deviations will be summarized by treatment group. 
 
Major protocol deviations include, but are not limited to: 
 
• 
Subjects who did not meet inclusion/exclusion criteria or eligibility was not 
adequately verified 
• 
Received prohibited concomitant medications post-baseline 
• 
Developed withdrawal criteria but were not withdrawn 
• 
Has a dosing error likely to impact key outcome measures (for example subject 
did not receive the medication they were randomized to receive) 
 
5. 
Efficacy Endpoints and Covariates 
 
 
5.1. 
Primary Efficacy Endpoint 
 
The primary endpoint is DFS, defined as the time interval (measured in years) from the date of 
randomization to the first date of recurrence (distant or local recurrence of RCC) or the 
occurrence of a secondary malignancy or death due to any cause. The primary DFS analysis will 
be based on assessment by the IRC. The IRC will review all available scans and in cases for 
which there is site confirmation of recurrence or occurrence of a secondary malignancy in the 
absence of IRC imaging confirmation, available local histo-/cytopathology reports will be 
reviewed by an independent IRC oncologist.   
 
 
Recurrence refers to relapse of the primary tumor in situ or at metastatic sites. The date of 
recurrence or the occurrence of a secondary malignancy is defined as the earlier of: 
• 
the date of the tumor scan or  the date of collection of the histo-/cytopathological 
specimen (for subjects who have site confirmed recurrence or occurrence of a secondary 
malignancy in the absence of IRC imaging confirmation) that demonstrated unequivocal 
recurrence or a second malignancy according to protocol criteria   
 
Per the IRC charter, radiological findings should be unequivocal.  At the time of the final IRC 
review for a given data cut (interim or final), equivocal disease, identified by radiology requiring 
confirmation, is noted in the IRC data at the ‘Global Review’ with an indication of disease 
present and a date of recurrence/secondary malignancy recorded by the IRC as not applicable 
(N/A).  As these findings require confirmation, they will not be counted as events in the DFS 
analysis unless, there is a subsequent pathology report which provides confirmation of the 
disease seen on the scan.  In this case the scan date should be used as the date of recurrence or 
secondary malignancy. 
 
In the absence of pathology to confirm the equivocal findings, these subjects will be censored at 
the date of last scan before anti-cancer therapy (if applicable).  The last scan date includes the 
scan where the equivocal finding was noted.   
 
For subjects identified as having the presence of disease at baseline by IRC review, 
• 
Recurrence will be considered to have occurred on the date of randomization. 


 
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For subjects with no DFS event, DFS time will be censored  
• 
at the date of last IRC reviewed scan prior to the time of the final analysis.  
• 
Subjects alive who do not have any post-baseline disease assessments will have their 
DFS times censored at randomization. 
 
For any subject who receives  anti-tumor therapy,  
• 
DFS will be censored on the date of the last IRC reviewed scan prior to taking the anti-
tumor therapy. However, in cases where there is no scan prior to anti-cancer therapy 
medication that was received after randomization, subjects will be censored at the date 
of randomization. 
 
For subjects who had two or more consecutively missed or not readable IRC reviewed scans 
immediately prior to a recurrence or occurrence of a secondary malignancy or death,  
• 
DFS will be censored on the date of the last IRC reviewed scan prior to the 
consecutively missed or not readable IRC reviewed scans.  
 
The length of DFS will be calculated as follows: 
             DFS (years) = [date of recurrence, secondary malignancy, or death or censor date – 
randomization date + 1]/365.25. 
 
5.2. 
Secondary Efficacy Endpoint 
 
Overall survival (OS) is defined as the time from the date of randomization to the date of death 
due to any cause.  In the absence of confirmation of death, survival time will be censored at the  
last date the subject is known to be alive.  Subjects lacking data beyond randomization will have  
their survival times censored at randomization. 
 
The length of OS will be calculated as follows: 
OS (years) = [death date or last known alive date – randomization date + 1] 
/365.25. 
 
 
 
5.3. 
Safety Endpoints 
 
Adverse Events 
 
Assessment of adverse events will include: type, incidence, severity (graded by the National 
Cancer Institute [NCI] CTCAE, Version 4.03), timing, seriousness, and relatedness. Laboratory 
abnormalities will be recorded as an adverse event in accordance with the criteria in Section 8.4 
of the protocol. 
 
Baseline tumor-related signs and symptoms will be recorded as adverse events during the trial if 
they worsen in severity or increase in frequency. 
 


 
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Laboratory Safety Assessments 
 
Hematology and blood chemistry will be drawn and urinalysis performed at the time points 
described in the Schedule of Activities and analyzed at local laboratories (Refer to Appendix 1 of 
the protocol).  Investigators may have additional blood tests performed for the purpose of 
planning treatment administration, dose modification, or following adverse events, and these 
should be repeated as clinically needed.  Prothrombin Time/International Normalizing Ratio 
(INR) should be performed to monitor subjects receiving concomitant warfarin or other anti-
coagulants and when clinically indicated. 
 
Thyroid Function Tests (Thyroid Stimulating Hormone [TSH], free T3 and free T4) should be 
performed for all subjects at baseline (Cycle 1 Day 1 pre-dose). Subsequently, TSH should be 
done at Cycle 1 Day 15, Cycle 2 Day 1, Cycle 3 Day 1, Cycle 4 Day 1, Cycle 5 Day 1, then every 
8 weeks thereafter starting from Cycle 7 Day 1. TSH, free T3 and free T4 should be done on the 
next visit for any subject who has an elevated TSH in the previous visit. Hypothyroidism should 
be treated per standard medical practice to maintain euthyroid state with a normal TSH. 
 
Other Safety Assessments 
 
Other safety assessments to be assessed include: physical examinations, 12-lead 
electrocardiogram (ECG) (recorded at Screening only), height (recorded at Screening only), 
weight, vital signs (recorded at clinical study visits) and ECOG PS. 
 
5.4. 
Covariates 
 
5.4.1. 
Stratification Factors 
 
As described in Section 3.2.2, randomization in this study is stratified by risk groups based on the 
AJCC TNM staging version 2010, ECOG PS and by country. Analyses for the primary and 
secondary endpoints as well as sensitivity analyses will be conducted based on analyses stratified 
by risk group only. Country will not be used as a stratification factor in analyses due to the 
limited number of subjects anticipated to be enrolled in some countries. Additional supportive 
analyses will not be stratified.  
 
In the event a subject was randomized to the incorrect strata, the strata used for analysis will be 
obtained from the IWRS.  
 
 
6. 
Statistical Methods  
 
6.1. 
General Methodology 
 
SAS version 9.2 or higher will be used in the statistical analysis. 
 
The level of significance for the analysis of the primary variable at the interim and final analysis 
stages are described in Section 6.3.  95% confidence intervals (CIs) will be employed where 
appropriate  


 
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Data for subjects who failed screening will be listed. This may include demographics, 
inclusion/exclusion criteria responses and reason for screen failure. 
 
 
6.1.1. 
Analyses for Continuous Data 
 
 
For continuous data, the following summary statistics will be presented: n, mean, standard 
deviation (StD), median, minimum and maximum.  
Mean and median values will be reported to one decimal place greater than the original data they 
were collected from while the StD will be reported to two decimal places greater than the original 
data. Minimum and maximum values will be reported with the same precision as they were 
collected. 
6.1.2. 
Analyses for Categorical Data 
 
For categorical variables, statistical summaries will include counts and absolute or relative 
percentages. The number of missing values will be presented where necessary. 
Percentages will be reported to 1 decimal place. Percentages will be calculated using a denominator 
of all subjects in a specified population. 
For by-visit analyses e.g. shift from baseline in toxicity grade of laboratory parameters only 
subjects with a measurement available will be included in the denominator for that visit. 
 
 
6.1.3. 
Analysis of Time-To-Event Endpoints 
 
Time-to-event endpoints will be summarized using the Kaplan-Meier method and displayed 
graphically when appropriate.  Median event times and 2-sided 95% CI for each median will be 
provided based on the Brookmeyer-Crowley2 method.   
Difference in time-to-event endpoints will be tested using a 2-sided stratified or unstratified log-
rank test, where applicable.  The stratified analysis will be performed as stated in Section 5.4.1.    
Cox proportional hazards model will be used to estimate the hazard ratio and its 95% CI.   
A parametric model will also be implemented as a sensitivity analysis of DFS. 
 
 
6.2. 
Handling of Dropouts or Missing Data 
 


 
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Subjects who discontinue study treatment will continue to be followed-up for DFS and OS until 
the time they have an event, or until the time of final analysis for DFS and OS. Subjects who 
withdraw from the study and are lost to follow-up will not be replaced.  Surviving subjects 
without a DFS event and/or OS event at the time of the final analysis will have their DFS 
censored as described in Appendix A.  All other missing data will be left as missing with the 
following exception as described in Section 6.2.1. 
 
 
6.2.1. 
Missing Data in Adverse Event Dates 
 
Missing dates in adverse events will be imputed as described below:  
 
• 
For the start date, if the day of the month is missing, the 1st day of the month will be 
used to replace the missing date unless it is the month of the first dose.  In that case, the 
start date will be imputed as the first dose date. If both day and month are missing, the 
1st of January of the non-missing year will be used to replace the missing date unless 
the non-missing year is the same year as first dose in which case the start date will be 
imputed as the first dose date. 
• 
For the stop date, if the day of the month is missing, the last day of the month will be 
used to replace the missing date. If both day and month are missing, December 31 of 
the non-missing year will be used to replace the missing date. 
 
If the start date is missing for an adverse event, the adverse event is considered to be treatment-
emergent. 
 
 
6.2.2. 
Missing Data in Safety Endpoints 
 
The percentage of subjects with an adverse event will be calculated using the number of as-
treated subjects as the denominator.  Therefore, no subjects in the as-treated population are 
excluded from adverse event displays.  The denominator for summary tables for each laboratory 
parameter will be all subjects in the as-treated population with at least one evaluable cycle for 
that parameter.  Different laboratory parameters may have different denominators, depending on 
the number of evaluable subjects for each parameter.  An evaluable cycle is any cycle with at 
least one assessment of that parameter.  Therefore, subjects with no assessments of a particular 
laboratory parameter are not included in the analysis of that parameter. 
 
 
6.3. 
Interim Analysis and Data Monitoring Check spending function 
 
A single interim analysis (IA) is planned for this study. O’Brien – Fleming type stopping 
boundaries based on the Lan-DeMets spending function will be applied to the primary endpoint 
DFS (as assessed by IRC).  Futility criteria are not used to calculate the nominal alphas (non-


 
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binding method) in order to control the overall Type I error.   
 
The  IA will take place after the first 184 events (75% of planned DFS events as assessed by the 
IRC) have occurred. If the event occurrence pace is much slower than anticipated, the IA could 
be performed with less than 184 events observed (<75% of the total required) at the sponsor’s 
discretion with the Data Monitoring Committee’s consensus. 
 
The objectives of the IA are: 
 
• 
To assess safety, including unexpected toxicity. 
• 
To allow for early stopping of the trial due to futility. 
• 
To allow for early stopping of the trial due to efficacy. 
 
 
If the results of the IA demonstrate statistically significant differences between the 2 treatment 
arms for DFS (in favor of the active drug), the sponsor, in consultation with HRAs, will 
disseminate the results of the trial, and the IA may be considered the final analysis for DFS. The 
nominal level of significance for the interim analysis of DFS determined using the Lan DeMets 
procedure with an O’Brien Fleming type stopping rule will be 0.0194 (2-sided; if the interim 
analysis is performed at 184 events). 
 
 
The descriptive safety analysis as described in Section 7.5 will be presented to assess any 
toxicities. 
 
The nominal significance level for the interim futility analysis of DFS will be determined using 
an O’Brien-Fleming stopping boundary.  The futility p-value boundary is specified in the table 
below.  If the calculated futility p-value is greater than the pre-specified boundary shown in the 
table below, the sponsor may choose to stop the trial for futility.  The associated critical hazard 
ratio is also provided in the table below for reference. 
 
Futility Stopping Boundary (non-binding) for DFS for Rejecting Alternative Hypothesis 
Expressed as HR and p-value 
Analysis 
Fraction of 
DFS Events 
Number of DFS 
Events 
HR 
(Axitinib:Placebo) 
2-sided  
p-value 
Interim 
75% 
184 
0.836 
0.2255 
 
 
The overall nominal significance level for the efficacy analysis of DFS will be preserved at 0.05 
(2-sided test).  To protect the integrity of the study and to preserve the type 1 error, a fraction of 
alpha will be spent at the interim analysis based on an O’Brien-Fleming stopping boundary.   The 
efficacy p-value boundaries are specified in the following table. The associated critical hazard 
ratio is also provided in the table below for reference. 
 
 
 
 


 
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Efficacy Stopping Boundary for DFS for Rejecting Null Hypothesis Expressed as  
HRs and p-values 
Analysis 
Fraction of 
DFS Events 
Number of DFS 
Events 
HR 
(Axitinib:Placebo) 
2-sided 
p-value 
Interim 
75% 
184 
0.708 
0.0194 
Final 
100% 
245 
0.773 
0.0442 
 
 
The actual nominal α levels for the interim analysis and for the final analysis will depend on the 
fraction of total events occurred at the time of the IA. 
 
 In addition to DFS based on IRC assessment, Kaplan-Meier summaries for DFS (according to 
investigator assessment) and OS will be presented for each treatment group. 
 
The primary endpoint of DFS is based on IRC assessment.  DFS based on investigator 
assessment is an important sensitivity analysis.  Although no formal hypothesis testing is 
planned for DFS based on investigator assessment, regulatory feedback has indicated the 
importance of consistency between investigator and IRC assessments of DFS.  Therefore, in 
order to meet the criteria for stopping for efficacy at the time of the interim analysis the same p-
value stopping criteria, determined based on the proportion of IRC assessed events at the time of 
the interim analysis out of the planned 245 events for the final analysis, will be applied to DFS 
based on investigator assessment.  Specifically, both the primary DFS analysis by IRC 
assessment and the DFS analysis by investigator assessment must meet the stopping criteria to 
stop for efficacy at the time of the interim analysis.  Assuming 184 IRC assessed events at the 
time of the interim analysis both the IRC and investigator DFS 2-sided p-values will be required 
to fall below 0.0194 to stop the study for efficacy.   The stopping rule for futility will only be 
applied to the primary DFS analysis by IRC assessment. 
 
 
Although there is no intention to perform any hypothesis test for OS at the interim analysis, a 
nominal α of 0.0001 will be allocated to the analysis of OS at the interim. The overall nominal 
significance level for the efficacy analysis of OS will be preserved at 0.05 (2-sided test). 
 
Note that for the interim analysis, the data will be initially presented to members of the DMC and 
designated unblinded personnel only. Decisions and recommendations based on the interim 
analysis review will be disseminated to the sponsor. The sponsor at that time may review and 
discuss the DMC recommendations with a second panel of independent experts. 
 
There are also planned regular reviews of the safety at separate DMC meetings as needed. Safety 
data will be summarized as described in Section 7.5. The timing and details of the DMC review 
are detailed in the DMC charter. 
 
6.4. 
Multicenter Studies 
 
No adjustment will be made in any analyses for center. 
 


 
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6.5. 
Multiple Comparisons/Multiplicity 
 
For the interim analysis performed and the final analysis for the primary endpoint of DFS, the 
significance level has been set using the O’Brien-Fleming method.  Although there is no 
intention to perform any hypothesis test for OS at the interim analysis, a nominal α of 0.0001 will 
be allocated to the analysis of OS at the interim. There will be no other adjustments for multiple 
testing. 
 
7. 
Statistical Analysis 
 
 
7.1. 
Analysis of Primary Efficacy Endpoint 
 
7.1.1. 
Disease-Free Survival Based on IRC Review 
 
Disease-Free Survival of the ITT Population based on the IRC review of tumor assessments will 
be summarized using the Kaplan-Meier method.  Kaplan-Meier curves for each arm will be 
generated, and median DFS time will also be presented with corresponding 95% CI. The CI for 
the median will be calculated according to Brookmeyer and Crowley2. To test the equality of 
DFS time in each arm a stratified log-rank test (using a stratification factor as defined in Section 
5.4) will be used.  Censoring rules as described in Table 1 of Appendix A will be implemented. 
The statistic of the test will be presented along with the associated two-sided p-value. 
 
The estimated HR (Axitinib/Placebo) will be obtained using a Cox’s Proportional Hazards 
model with treatment group as well as a randomization stratification factor as a covariate. The 
stratification factor used in the analyses will be risk group as described in Section 5.4.1. 
 
The significance level for the final DFS analysis will be 0.0442 as calculated using the 
O’Brien-Fleming method.  (Assumes interim analysis at 184 events with a significance level of 
0.0194). 
 
Annual DFS rates up to 5 years for each treatment group will be estimated and presented with 
corresponding 95% CI. The CI for the survival function will be calculated using the 
complementary log-log transformation method. 
 
The final analysis of the primary endpoint of DFS will be performed when approximately 245 
DFS events based on IRC review are observed. 
 
A subject listing for DFS will include, DFS time, censoring status, censoring reason, date of 
randomization and date of last tumor assessment.  In addition, a listing of subjects with baseline 
disease as determined by the IRC, will be produced. 
 
 
7.1.2. 
Methods for Evaluating the Validity of Model Assumptions 
 


 
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Schoenfeld residuals for the stratified Cox proportional regression model will be plotted to 
investigate graphically violations from the proportional hazards (PH) assumption for the primary 
DFS endpoint; a non-zero slope is evidence of departure from PH. The PH assumption will be 
formally tested using Schoenfeld’s residual test (Schoenfeld, 1980; Therneau and Grambsch, 
2000)3.  Large departures from PH will be evidenced by a p-value < 0.05.  
In addition, the proportional hazards assumption will be checked visually by plotting  
-log(log(S(t)) versus log(t),  
where S(t) is the estimated survival function at time t. 
If these assessments show large departures from proportional hazards, then DFS may also be 
analyzed based on the test of RMST(τ) differences between treatment arms based on the stratified 
Cox regression model as described in Zhang (2013)4.  
 
The RMST up to time t* can then be interpreted as the expected survival time restricted to the 
common follow-up time t* among all patients.  Analyses will be repeated using the follow 
criteria to define t*: 
• 
t*1 = min of (longest observed survival time for experimental arm, longest observed 
survival time for control arm) in years 
• 
t*2= min of (longest event time for the experimental arm, longest event time for the 
control arm) in years 
• 
t*3 = the midpoint between the numbers t*1 and t*2 
RMST can be estimated consistently by the area under the Kaplan-Meier curve over [0, t*].  The 
treatment effect between each of the experimental arms and the control arm will be assessed 
based on the difference in RMST. The associated 95% CI for the difference in means and two-
sided p-value will be generated.  RMST as a function of t* and the associated treatment effect 
between each of the experimental arms and the control arm will be plotted against time t*. 
 
Note RMST was not specified in the protocol.  This was added to the SAP as an exploratory  
analysis. 
 
7.2. 
Analysis of Secondary Efficacy Endpoint 
 
7.2.1. 
Overall Survival  (OS) 
 
OS of the ITT Population will be analyzed  in the same way as the primary endpoint.  Censoring 
rules as described in Table 2 of Appendix A will be implemented. At the time of final analysis of 
DFS, a hypothesis test on OS will be conducted at two-sided alpha = 0.0499 only if DFS is 


 
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declared statistically significant.  
 
7.3. 
Additional Analyses of Efficacy 
 
All additional analyses of efficacy will be performed on the ITT Population unless otherwise 
specified. 
 
 
7.3.1. 
Sensitivity Analyses 
 
The following sensitivity analyses will be performed: 
 
• 
Investigator Assessed DFS: DFS defined in a similar manner as defined for the primary 
analysis, but based on local investigator assessment rather than IRC assessment (Refer to 
Table 3 of Appendix A for censoring rules.) For this analysis tumor imaging assessments 
as well as histo-/cytopathology information will be used to assess disease recurrence or 
occurrence of secondary malignancy. If both imaging and histo-/cytopathological 
confirmation of recurrence or occurrence of secondary malignancy are available, the 
earlier of the two dates will be considered. In addition, discordance rates between IRC 
review and investigator assessments using methods described by Amit et al.5 will be 
summarized in a table. Calculations will be as follows: 
 
 
IRC Review
Investigator 
Assessment 
(INV) 
Recurrence or 
secondary 
malignancy or 
death 
No recurrence or 
secondary 
malignancy or 
death 
Recurrence 
or 
secondary 
malignancy 
or death 
a = a1 + a2 + a3 
b 
No 
recurrence 
or 
secondary 
malignancy 
or death 
c 
d 
 
a1: number of agreements on timing and occurrence of event;  
a2: number of times agreement on event but INV declares event later than IRC Review;  


 
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a3: number of times agreement on event but INV declares event earlier than IRC 
Review;  
 N= a+b+c+d.  
 
The following measure of discordance will be calculated per arm: 
 
• 
Total Event Discrepancy Rate: (b+c) / N 
• 
Early Discrepancy Rate (EDR): (a3+b) / (a+b) 
• 
Late Discrepancy Rate (LDR): (a2+c) / (a2+a3+b+c) 
• 
Overall Discrepancy Rate: (a2+a3+b+c) / N 
A window of 28 days will be used in determining agreement on timing of an event.  Specifically, if 
the data or recurrence by the IRC is within  +/- 28 days of the data of recurrence by the 
investigator these cases will be considered as ‘agreement on the timing and occurrence or an 
event’. 
• 
DFS based on IRC Without Censoring for New Cancer Therapy or Missed Assessments: 
DFS based on IRC review, as defined for the primary analysis, but without censoring 
subjects who: 
o 
 receive further anti-tumor therapy, or 
o 
 have two or more consecutively missed or not readable scans immediately prior to 
recurrence, or occurrence of a secondary malignancy, or death.  
In other words, a subject who meets the above criteria will be assigned a DFS event at the 
first date of recurrence or occurrence of a second primary cancer or death. In the absence 
of a DFS event, DFS time will be censored at the date of last scan prior to the time of 
analysis.  Subjects alive who do not have post-baseline disease assessment will have their 
DFS times censored at randomization. (Refer to Table 4 of Appendix A for censoring 
rules.)   
• 
Start of New Anti-tumor Therapy as DFS Event: DFS based on IRC review, as defined 
for the primary analysis, but utilizing the start date of new anti-tumor therapy as a DFS 
event. (Refer to Table 5 of Appendix A for censoring rules.)  
 
• 
DFS at Scheduled Assessments:  DFS based on IRC review, as defined for the primary 
analysis, but instead assigning the dates for events and censoring at the scheduled scan 
dates instead of the actual scan dates. Specifically, events that occur within +/- 4 weeks of 
a scheduled scan will be considered an event at the scheduled scan. Events outside the 4-
week window will be counted as events at the next scheduled scan time and censoring 
outside the 4-week window would be censored at the previous scheduled scan. If, 
however, the event is death or disease at baseline, the date of death or date or 
randomization respectively will be used as the event date unless anti-tumor therapy was 


 
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received prior to the date of death in which case the subject will be censored at the 
scheduled scan prior to the date of anti-cancer therapy or for subjects who have two or 
more missed or not readable consecutive tumor scans immediately followed by an event 
will be censored on the date of their most recent scheduled scan prior to the missing/not 
readable scans. (Refer to Table 6 of Appendix A for censoring rules.) 
• 
DFS with Interval-censoring: DFS based on IRC review as defined for the primary 
analysis will be performed with a parametric model utilizing techniques for interval-
censored data. Graphical diagnostics will be used to select the distribution of the 
parametric model that best fits the data.  Intervals of 16 weeks will be implemented for 
censoring purposes (Refer to Table 7 of Appendix A for censoring rules.) 
 
7.3.2. 
Subgroup Analyses 
 
 
In addition, DFS by IRC will be analyzed in the same way as the primary analysis for the 
following subgroups with the exception that there will be no stratification variable in the model 
due to small numbers of subjects:   
 
• 
Risk group  
i. 
a (pT2/pN0 or pNX/M0) 
ii. 
b (pT3/pN0 or pNX/M0) 
iii. 
c (pT4/pN0 or pNX/M0) 
iv. 
d (Any pT/pN1/M0) 
v. 
c+d combined  
vi. 
High Risk ([b with Fuhrman grade 3 or 4]+c+d)  
vii. 
Low Risk (a+[b with Fuhrman grade 1 or 2]) 
• 
Age (<65, >=65 years) 
• 
Race 
• 
Gender 
• 
Baseline ECOG PS (0 vs >=1) 
• 
Baseline Weight 
viii. 
Normal (18.5<=body mass index (BMI)<25) 
ix. 
Overweight + Obese (BMI>=25) 
x. 
Overweight (25<=BMI<30) 
xi. 
Obese (BMI>=30) 
• 
Baseline neutrophil to lymphocyte ratio (NLR) (NLR>3 vs. NLR<=3) 
• 
Fuhrman Grade (1&2 vs. 3 &4) 
 
 
 
 


 
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7.3.3. 
Post hoc Analyses 
 
In addition to the overall analysis, all efficacy and safety analyses may later be presented by 
country in order to produce results to be included in Japan, China, Korea and Taiwan sub-
population reports. The decision to pursue these analyses will be determined by SFJ depending 
upon availability of subjects within country strata. There are no other planned subset analyses in 
this study. 
 
 
7.3.4. 
Exploratory Analyses 
 
Exploratory analyses may be performed as deemed appropriate.   
 
RMST for DFS may be explored if non-proportional hazards are observed for the primary 
endpoint. 
 
DFS and Treatment Duration:  A one-year landmark analysis will be performed to explore the 
association between extended treatment with Axitinib and DFS. Patients randomized to Axitinib 
will be divided into 2 groups based on treatment status at 1 year.  Namely patients whose 
duration of treatment in less than or equal to one year will be compared to those whose duration 
of treatment is greater than one year.  Only patients randomized to treatment with Axitinib who 
are alive, disease-free, and still in disease-free survival follow-up at one year will be included in 
the analysis.  Specifically, patients who had disease recurrence, secondary malignancies, died, or 
were otherwise censored for DFS due to start of new anticancer therapy, missed assessments, or 
lost to follow-up prior to one year will be excluded from the analysis.   Median event times and 
2-sided 95% CIs for each median will be provided based on the Brookmeyer-Crowley 
method.  Cox proportional hazards model will be used to estimate the unstratified hazard ratio 
and its 95% CI.   A p-value will not be reported as this analysis is considered exploratory. 
 
 
Treatment Discontinuations due to AEs of Interest: an evaluation of cumulative incidence of 
treatment discontinuations for defined AEs of interest will be conducted. A summary table will 
be provided.  A figure displaying the proportion of subjects off treatment over time will be 
provided for subjects randomized to axitinib or placebo who experienced various defined 
adverse events of interest. 
 
 
7.4. 
Standard Analyses 
 
7.4.1. 
Disposition of Subjects 
 
Subject disposition, including the number of subjects enrolled, number of subjects treated, 
number of subjects evaluated for safety and number of subjects who completed the study or 
withdrew early (including reasons for withdrawal) will be summarized by treatment group for the 
ITT population. 
 
Disposition information will be listed. 


 
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7.4.2. 
Demographic and Other Baseline Characteristics 
 
The following demographic and baseline characteristics will be summarized for the ITT 
population. 
 
Demography: Gender, age (calculated from date of birth and date of screening visit), height, 
weight (at screening), BMI (at screening), ECOG PS (at screening) and race. 
 
Primary Diagnosis: Body Site, time since date of histopathological diagnosis (calculated as 
number of years from date of histopathological diagnosis to date of screening visit), histological 
classification, risk group. 
 
Medical History: Medical history will be coded using the latest version of Medical Dictionary 
for Regulatory Activities (MedDRA) and summarized by system organ class (SOC) and 
preferred term (PT). 
 
Prior Medication/Therapy: Prior medications, as defined in Section 7.5.5, will be summarized by 
the Anatomical Therapeutic Chemical (ATC) Classification System and WHO Drug name.  Prior 
non-drug treatments, as defined in Section 7.5.5, will be provided in a listing.  
 
Signs and Symptoms: Signs and symptoms are defined as any events recorded in the medical 
history page ongoing at screening.  They will be summarized by SOC and PT.  
 
7.4.3. 
Extent of Exposure 
 
Study treatment exposure will be summarized for all subjects in the as-treated population. The number of 
subjects who completed at least 3 years of study medication, at least 2 years of study medication and at 
least 1 year of study medication will be provided.  Duration of exposure to study medication will be 
calculated as the number of months from date of first dose to date of last dose + 1 day.  For the purposes 
of categorization of exposure duration, the following conversions (assuming a -14 day window) will be 
used: 
• 
1-351 days = “0 - <12 months”    
 
  
• 
352-716 days = “12 - <24 months” 
• 
717-1081 days = “24 - <36 months” 
• 
>1081 days= “≥36 months”. 
 
 
Reasons for treatment withdrawal will be provided. 
 
Overall duration of exposure to study medication will be summarized by treatment group using 
summary statistics. 
 
Also, the total dose prescribed in milligrams (mg) and the actual dose administered will be 
summarized. 
 
Number and percentage of subjects with dose increases, dose reductions and dose interruptions  


 
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will be summarized. 
 
 
Other summaries will include: 
 
• 
Descriptive statistics for time to the first actual dose interruption, dose 
reduction and dose increase 
 
• 
Descriptive statistics for time to the second actual dose interruption, dose 
reduction and dose increase 
 
• 
Descriptive statistics for time to the third actual dose interruption, dose 
reduction and dose increase 
 
• 
Descriptive statistics for time to first dose interruption, time to first dose 
interruption that was   ≥7 days, ≥ 14 days, and  ≥21 days after first dose date. 
The time to dose interruption is calculated as (start date of the interruption – 
first dose date + 1).   
 
• 
Descriptive statistics for time to second dose interruption, time to second dose 
interruption that was ≥7 days, ≥14 days, and  ≥21  days after first dose date. 
 
• 
Relative dose: percent of actual total dose received relative to intended total 
dose initially planned per protocol (5mg BID), where actual total dose= total 
dose received as recorded on CRF, and intended total dose = (prescribed dose 
at beginning of the study)×(actual dose duration). 
 
 
 
7.5. 
Analysis of Safety 
 
All safety analyses will be performed using the As-Treated population. No formal comparisons 
between the two treatment arms are planned. Safety and tolerability will be assessed by the 
incidence of treatment emergent-adverse events (TEAEs), changes in laboratory parameters and 
vital signs from baseline, and ECG. 
 
An independent DMC will monitor safety during the study on a regular basis. The committee will 
operate independently from the Sponsor and the clinical investigators. 
 
The primary responsibility of the DMC is to review the accumulating safety data on a regular and 
an ad hoc basis and make recommendations to the Sponsor regarding the continued conduct of 
the study. Safety data will be provided at regular intervals to the DMC in the form of summary 
reports or data listings from the Sponsor or its designated representative. 
 
Details regarding DMC membership, schedule and format of meetings, format for presentation of 
data, access to interim data, method and timing of providing interim reports to the DMC, and 


 
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other issues relevant to committee operations are described in the DMC charter. 
 
The DMC members will use their expertise, experience, and judgment to evaluate the safety data 
from the trial and to recommend to the Sponsor whether the trial should continue or be stopped 
early for safety.  
 
 
7.5.1. 
Adverse Events 
 
 
Adverse event (AE) terms recorded on the CRF will be mapped to PT and SOC using the 
Medical Dictionary for Regulatory Activities (MedDRA ). The severity of AEs will be evaluated 
by the investigator by employing the CTCAE v4.03 (Cancer Terminology Criteria for Adverse 
Events). The investigator will also judge each event to be “not related” or “related” to study 
treatment. 
 
A TEAE is defined as any AE with an onset date on or after the date of the first dose of study 
treatment or any ongoing event on the date of the first dose of study treatment that worsens in 
severity after the date of the first dose of study treatment.  
 
The AE observation period is defined as the time from date of the first dose of study treatment 
until 28 days after the last dose of study drug is administered.  TEAEs with an onset date through 
the end of the study observation period will be summarized by treatment arms.  The Grade 5 
TEAEs with onset date outside of the observation period may be tabulated separately.   
 
 
For summaries of subject incidence of TEAE, at each level of summarization, a subject will be 
counted only once for each AE preferred term experienced by the subject within that level 
(i.e., multiple episodes of events with the same preferred terms will be counted only once). 
Selected summaries of subject-incidence of AEs (as defined in Section 7.5.1.2) will include the 
risk difference (defined as the proportion with the event in the axitinib arm minus the proportion 
with the event in the placebo treatment arm) with 95% CIs and the risk ratio (or relative risk; 
defined as the proportion with the event in the axitinib group divided by the proportion with the 
event in the placebo group) with 95% CIs. An overall summary of treatment emergent adverse 
events (including those that stopped more than 28 days after the decision to discontinue study 
treatment) will be provided with the number and percent of subjects who experienced the 
following in each treatment group: 
 
• 
Subjects with a TEAE  
• 
Subjects with a Related TEAE  
• 
Subjects with a Serious TEAE at any time (including active treatment period 
plus follow-up period) 
• 
Subjects with a Serious Related TEAE  
• 
Subjects with a Worst-Grade of >=3 TEAE 
• 
Subjects with a Worst-Grade of >=3 Related TEAE  
• 
Subjects with a Grade 5 TEAE at any time 


 
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• 
Subjects with a Grade 5 TEAE through 28 days of last dose of the study 
treatment  
• 
Subjects with a Related Grade 5 TEAE at any time 
• 
Subjects with a TEAE leading to dose modification (dose reduction or 
temporary interruption/discontinuation)  
• 
Subjects with a TEAE leading to dose reduction  
• 
Subjects with a TEAE leading to temporary dose interruption/discontinuation 
• 
Subjects with TEAE leading to permanent discontinuation 
 
 
 
7.5.1.1 
Deaths 
All reported subject deaths and whether death was causally associated with the disease under 
study will be summarized by treatment arm in the as-treated population.     
 
Deaths will be summarized in 2 main categories as follows: 
 
• 
Deaths within 28 days after the date of receipt of the last dose of study 
treatment  
• 
Deaths greater than 28 days after the date of receipt of last dose of study 
treatment   
 
Summary of primary cause of death will be tabulated causality to study disease and relationship 
to study drug.  
 
7.5.1.2 
Treatment Emergent Adverse Events of Special Interest 
The following TEAEs of special interests will be summarized for the as-treated population and 
by SOC and PT for each categorized treatment group.  The list of MedDRA defined SOCs and 
PTs for TEAEs of special interest are provided below and may be updated at the time of database 
lock based on the MedDRA version in use at the time of reporting and/or any additional safety 
information available from the Axitinib program that may determine a need to consider 
additional events of interest. Additionally, for the following special adverse events, 
Kaplan-Meier methods will be used to display the time to the first occurrence of each of these 13 
event categories, if the number of events is >=10 events per treatment arm:  
 
Adverse Events of 
Special Interest 
Search Terms (MedDRA version 20.1)
Cardiac disorders 
Cardiac disorders – SOC
Cardiac and vascular investigations (excluding enzyme tests)- HLGT     
Nervous system 
disorders 
Central nervous system vascular disorders- HLGT
Vascular disorders 
Embolism and thrombosis- HLGT
Pulmonary Embolism PT
Renal vascular disorders 
Renal vascular and ischaemic conditions (HLT)
Renal failure and impairment (HLT) 
Renal hypertension and related conditions (HLT)


 
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Haemorrhage 
Haemorrhage (excluding lab terms) SMQ (broad and narrow) and Haemorrhage 
laboratory terms SMQ (broad and narrow)
Hypertension 
Hypertension SMQ narrow
Proteinuria 
MedDRA PTs: Albumin urine present, Proteinuria, Protein urine, and Protein 
urine present
Thyroid Dysfunction 
Thyroid dysfunction SMQ broad
Venous Embolic and 
Thrombotic Events 
(VTE) 
Embolic and thrombotic events, venous SMQ narrow
Palmar-Plantar 
Erythrodysesthesia 
(PPE) 
MedDRA PTs: Palmar-plantar erythrodysesthesia syndrome, palmar erythema, 
and plantar erythema.   
Fatigue and Asthenic 
Conditions 
MedDRA PTs: Asthenia, Autonomic nervous system imbalance, Decreased 
activity, Listless, Sluggishness, Chronic fatigue syndrome, Fatigue and Malaise) 
Hepatic Disorders 
Cholestasis and jaundice of hepatic origin (SMQ narrow) 
Drug-related hepatic disorders - comprehensive search (SMQ narrow) 
Liver related investigations, signs and symptoms (SMQ narrow) 
Hepatic & Hepatobiliary disorders (HLGT)
Congestive Heart 
Failure/Cardiomyopathy 
MedDRA PTs: Acute left ventricular failure, Acute right ventricular failure, 
Cardiac failure, Cardiac failure acute, Cardiac failure chronic, Cardiac failure 
congestive, Cardiac failure high output, Cardiogenic shock, Cardiopulmonary 
failure, Chronic left ventricular failure, Chronic right ventricular failure, Cor 
pulmonale, Cor pulmonale acute, Cor pulmonale chronic, Ejection fraction 
decreased, Left ventricular failure, Low cardiac output syndrome, Neonatal 
cardiac failure, Right ventricular failure, Ventricular failure, Cardiac output 
decreased, Cardio-respiratory distress, Central venous pressure increased, 
Diastolic dysfunction, Left ventricular dysfunction, Myocardial depression, 
Oedema due to cardiac disease, Right ventricular dysfunction, Systolic 
dysfunction, Ventricular dysfunction, Cardiomyopathy acute, Congestive 
cardiomyopathy, Ejection fraction abnormal, Ejection fraction decreased. 
Carcinogenicity 
(Second Primary 
Malignancy) 
SMQ malignant or unspecified tumours, SMQ Malignant tumours, SMQ Tumours 
of unspecified malignancy and the Lower Level Term (LLT): Secondary primary 
malignancy.
For Cardiovascular disorders: Include Cardiac disorders, Nervous system disorders, Vascular disorders 
 
 
 
 
7.5.2. 
Clinical Laboratory Evaluation 
 
Laboratory tests to be performed, and timing of collection, are detailed in Section 7.2.2 of the 
protocol and include the following: 
 
 
• 
Hematology: Hgb, white blood cell count (WBC), absolute neutrophil count 
(ANC), lymphocyte count and platelet count.  


 
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• 
Chemistry: Total bilirubin, aspartate aminotransferase (AST), alanine 
aminotransferase (ALT), alkaline phosphatase, albumin, total protein, lactate 
dehydrogenase (LDH), sodium, potassium, chloride, calcium, phosphate, 
blood urea nitrogen (BUN)/Urea, creatinine, glucose.  
 
• 
Urine dipstick for protein (subjects with ≥2+ protein will have urine protein 
creatinine [UPC] ratios).  
 
• 
Pregnancy test, if applicable. Urine pregnancy test will be conducted at sites 
for females of childbearing potential only. If positive, then serum test should 
be conducted at central laboratories.  
 
• 
Thyroid Function: TSH, free T3 and free T4 
 
 
Baseline laboratory values will be selected from the date closest to but on or prior to the first 
dose (if there is more than one baseline evaluation).  
 
Summary statistics for actual values and change from baseline will be presented for all planned 
time points for Hematology, Chemistry, Urinalysis and Thyroid function tests. 
 
Shift from baseline to all post-baseline time points will be produced for urine protein. 
 
Shift from baseline to all post-baseline time points in toxicity grading will be produced for all 
laboratory parameters which are graded per NCI CTCAE, along with shift from baseline to worst 
toxicity grade (where worst toxicity grade is defined as the worst toxicity grade experienced at 
any post-baseline time point, including unscheduled assessments). For laboratory parameters that 
are graded in both directions e.g. “hyper” and “hypo”, separate rows will be presented for each 
directional assessment.  The hematologic and chemistry laboratory results will be graded 
according to the NCI CTCAE v4.03 severity grade. For parameters for which an NCI CTCAE v 
4.03 scale does not exist, the frequency of subjects with values below, within and above the 
normal range for the local lab will be summarized.  
 
A summary table of the proportion of subjects meeting Hy’s Law criteria will be provided. The 
following algorithm will be utilized to determine if Hy’s Law Criteria have been met: 
 
1) if ALT|AST baseline is missing, low or normal: Alkaline 
Phosphatase < 2*Upper limit of normal (ULN) AND Bilirubin >= 
2*ULN AND ALT|AST >= 3*ULN; 
 
2) if ALT|AST baseline is high: Alkaline Phosphatase < 2*ULN AND 
Bilirubin >= 3*ULN or (Bilirubin >= 2*ULN and Bilirubin >= 
ULN+Baseline) AND ALT|AST >= 8*ULN or (ALT|AST >= 
3*ULN and ALT|AST >= 2*Baseline) 
              
 A Hy’s Law Listing will be provided. 


 
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All laboratory results will be listed.  Any unscheduled laboratory assessments will be listed only. 
 
7.5.3. 
ECG Evaluations 
 
ECG evaluations are performed at screening only in this study. 
 
The number and percentage of subjects with Normal, Abnormal not Clinically Significant, 
Abnormal Clinically Significant and Unevaluable reading at screening will be summarized by 
treatment group. 
 
Summary statistics for QT Interval, Heart Rate, RR Interval, QT corrected for heart rate using 
Bazett’s method (QTcB) and QT corrected for heart rate using Fridericia’s method (QTcF) will 
be produced by treatment group using categories as defined in the International Conference on 
Harmonisation (ICH) E14 guideline (i.e., QTcF millimeter/second [ms]: ≤ 450; >450 - ≤ 480; 
>480-≤ 500; >500). 
 
All ECG results will be listed. 
 
7.5.4. 
Vital Signs,  Physical Findings, and Other Observations Related to Safety 
 
Baseline for body weight and vital signs will be defined as the latest value recorded on or prior 
to dosing on Day 1. Summary statistics for actual values and change from baseline will be 
presented.  Unscheduled body weight and vital signs measurements will be listed only. 
 
The proportion of subjects meeting the following blood pressure criteria on 2 or more scheduled 
and unscheduled visits (need not be consecutive) after first dose (modified from JNC criteria to 
address single measurement per time point) (Chobanian et al., 2003)6 will be presented in a 
table: 
 
• 
Normal: Systolic Blood Pressure (SBP) <120 mmHg and Diastolic Blood 
Pressure (DBP) < 80 mmHg 
• 
Pre-hypertension*: SBP 120-139 mmHg or DBP 80-89 mmHg 
• 
Stage 1: SBP 140-159 mmHg or DBP 90-99 mmHg 
• 
Stage 2: (SBP ≥160 mmHg and DBP <120) or DBP 100-119 mmHg 
 
*Defined according to CTCAE v4.03 criteria. 
 
The proportion of subjects with weight loss ≥10% after first dose will also be presented in a 
table. 
 
ECOG PS and change from baseline in ECOG PS will be summarized using summary statistics, 
and will also be presented as a shift from baseline to post-baseline time points. Specifically, shift 
tables of ECOG  score from baseline will be presented at each cycle as well as tables 
demonstrating from baseline to best and worst post baseline score. A mixed model will also be 
implemented to assess treatment differences in ECOG PS over time.  Baseline ECOG will be 


 
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included in the model as a covariate 
 
Physical examinations will be listed only. 
 
7.5.5. 
Prior/Concomitant Medications 
 
Prior and concomitant medications will be coded using the WHO-drug (World Health 
Organization) coding dictionary. 
 
Prior medications are defined as those medications stopped prior to the first day of study 
treatment.  Concomitant medications are defined as those medications either stopped, ongoing or 
started on or after the first day of study treatment up to 28 days post the last day of study 
treatment. 
 
Number and percentage of subjects taking all prior and concomitant medications will be 
summarized by ATC Class and WHO Drug Name.  
  
A listing will be provided for prior and concomitant non-drug treatments and procedures. 
 
Prior non-drug treatments and procedures are defined as those stopped prior to the first day of 
study treatment.  Concomitant non-drug treatments and procedures are defined as those 
treatments and procedures that are either stopped, ongoing or started on or after the first day of 
study treatment. 
 
Prior treatment for cancer under study (including drugs administered, start and stop date of each, 
and reason for taking the medication) will be provided in a listing. 
 
Anti-tumor drug treatments taken at follow-up will also be listed and summarized using the 
WHO-drug coding dictionary. Start dates to be considered as occurring during follow-up will be 
those that are >28 days beyond the last day of study treatment. 
 
 
 
  
 
8. 
References 
 
1. AG-013736 Protocol, Version 10, 21MAR2017. 
 
2. Brookmeyer R and Crowley JJ. A confidence interval for median survival time.  Biometrics, 
38, 29-41, 1982.  
 
3. Schoenfeld D. Chi-squared goodness of fit tests for the proportional hazards regression model. 
Biometrika, 1980, 67:145-153. 
 
4. Zhang, Xu. Comparison of restricted mean survival times between treatments based on a 
stratified Cox model. Bio-Algorithms and Med-Systems 2013; 9(4): 183–189. 
 


 
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5. Amit O, et al.  Blinded independent central review of progression in cancer clinical trials:  
Results from a meta-analysis and recommendation from a PhRMA working group. European 
Journal of Cancer 47:1772-1778, 2011. 
 
6. Chobanian AV, Bakris GL, Black HR et. al. The Seventh Report of the Joint National 
Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the 
JNC 7 report. JAMA, 2003, 289(19):2560-72. 
 
 
 


 
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9. 
Appendix A 
 
 
 
  
 
Table 1. Primary Endpoint Disease-Free Survival by Independent Review Committee 
 Censoring Rules: 
 
Date of event*/ censoring 
Censoring 
No IRC 
confirmed 
recurrence or 
occurrence of 
secondary 
malignancy or 
death 
Post baseline assessments 
performed 
Date of last IRC reviewed scan 
prior to receiving anti-tumor 
therapy, if applicable
Yes 
No post baseline 
assessments performed 
Date of randomization 
Yes 
IRC confirmed 
recurrence, 
secondary 
malignancy or 
death 
Baseline scan shows 
presence of disease 
Date of randomization 
No 
Further anti-tumor therapy 
received after randomization 
and before recurrence or 
occurrence of secondary 
malignancy or death 
(Subject does not have two 
or more consecutively 
missed/not readable IRC 
reviewed scans immediately 
prior to recurrence, 
secondary malignancy or 
death)** 
Date of last IRC reviewed scan 
prior to receiving anti-tumor 
therapy 
Yes 
Further anti-tumor therapy 
received after randomization 
and before recurrence or 
occurrence of secondary 
malignancy or death and 
subject had two or more 
consecutively missed/not 
readable IRC reviewed scans 
immediately prior to 
recurrence, secondary 
malignancy or death)**
Date of last IRC reviewed scan 
prior to the two consecutively 
missed/not readable scans and 
prior to receiving anti-tumor 
therapy** 
Yes 
No anti-tumor therapy 
received after randomization 
(Subject does not have two 
or more consecutively 
missed/not readable IRC 
reviewed scans immediately 
prior to recurrence, 
secondary malignancy or 
Date of IRC confirmed 
recurrence or occurrence of 
secondary malignancy or death, 
whichever occurred first* 
No 


 
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death)** 
No anti-tumor therapy 
received after randomization 
but subject had two or more 
consecutively missed/not 
readable IRC reviewed scans 
immediately prior to 
recurrence, secondary 
malignancy or death**
Date of last IRC reviewed scan 
before two consecutively 
missed/not readable IRC 
reviewed scans ** 
Yes 
* Note: For subjects for whom there is site confirmation of recurrence or occurrence of secondary 
malignancy in the absence of IRC imaging confirmation, the date of IRC confirmation from histo-
/cytopathology specimens will be selected as the date of event if available. For subjects for whom the IRC 
sees a finding on a scan that requires confirmation but an additional scan is not provided, if there is a 
subsequent pathology report available the pathology report could be the confirmation of the disease seen 
on the scan.  In this case the scan date should be used as the date of recurrence or secondary malignancy. 
 
**Additional details regarding the definition of two or more consecutively missed or inadequate scans 
can be found in Appendix B. For subjects who died prior to missing two scheduled assessments, they will 
be coded as an event at the date of death and will not be censored as long as no anti-tumor therapy was 
given after randomization and before death. 
 
 
 
Table 2. Secondary Endpoint Overall Survival Censoring Rules: 
 
Date of event/ censoring 
Censoring 
Alive  
Post baseline assessments 
performed 
Date subject last known to be 
alive
Yes 
No post baseline 
assessments performed
Date of randomization 
Yes 
Dead 
 
Date of death
No 
 
 
 
 
 
Table 3. Sensitivity Analysis Disease-Free Survival by Investigator Assessment 
Censoring Rules: 
 
Date of event/ censoring 
Censoring 
No Investigator 
confirmed 
recurrence or 
occurrence of 
secondary 
malignancy or 
death 
Post baseline assessments 
performed 
Date of last local imaging 
assessment prior to receiving 
anti-tumor therapy if applicable 
Yes 
No post baseline 
assessments performed 
Date of randomization 
Yes 
Investigator 
confirmed 
Baseline scan evaluated by 
the investigator shows 
Date of randomization 
No 


 
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recurrence or 
secondary 
malignancy or 
death 
presence of disease 
Further anti-tumor therapy 
received after randomization 
and before recurrence or 
occurrence of secondary 
malignancy or death 
(Subject does not have two 
or more consecutively 
missed local imaging 
assessments immediately 
prior to recurrence, 
secondary malignancy or 
death)* 
Date of last local imaging 
assessment prior to receiving 
anti-tumor therapy 
Yes 
Further anti-tumor therapy 
received after randomization 
and before recurrence or 
occurrence of secondary 
malignancy or death and 
subject had two or more 
consecutively missed local 
imaging assessments 
immediately prior to 
recurrence, secondary 
malignancy or death)*
Date of last local imaging 
assessment prior to the two 
consecutively missed scans and 
prior to receiving anti-tumor 
therapy* 
Yes 
No anti-tumor therapy 
received after randomization  
(Subject did not have two or 
more consecutively missed 
local imaging assessments)*
Date of investigator confirmed 
recurrence or occurrence of 
secondary malignancy or death, 
whichever occurred first 
No 
No anti-tumor therapy 
received after randomization 
but subject had two or more 
consecutively missed local 
imaging assessments*
Date of last local imaging 
assessment before two 
consecutively missed local 
imaging assessments* 
Yes 
 
*Additional details regarding the definition of two or more consecutively missed scans can be found in 
Appendix B. For subjects who died prior to missing two scheduled assessments, they will be coded as an 
event at the date of death and will not be censored as long as no anti-tumor therapy was given after 
randomization and before death. 
 
 
 
 
Table 4. Sensitivity Analysis Disease-Free Survival by Independent Review Committee without 
Censoring Subjects for Anti-tumor Therapy or for two or more consecutively missed or not 
readable scans 
Censoring Rules: 


 
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Date of event/ censoring 
Censoring 
No IRC 
confirmed 
recurrence or 
occurrence of 
secondary 
malignancy or 
death 
Post baseline assessments 
performed 
Date of last IRC reviewed scan 
Yes 
No post baseline 
assessments performed 
Date of randomization 
Yes 
IRC confirmed 
recurrence or 
occurrence of 
secondary 
malignancy or 
death 
Baseline scan shows 
presence of disease  
Date of randomization 
No 
 
Date of IRC confirmed 
recurrence or occurrence of 
secondary malignancy or death, 
whichever occurred first* 
No 
* Note: For subjects for whom there is site confirmation of recurrence or occurrence of secondary 
malignancy in the absence of IRC imaging confirmation, the date of IRC confirmation from histo-
/cytopathology specimens will be selected as the date of event if available. For subjects for whom the IRC 
sees a finding on a scan that requires confirmation but an additional scan is not provided, if there is a 
subsequent pathology report available the pathology report could be the confirmation of the disease seen 
on the scan.  In this case the scan date should be used as the date of recurrence or secondary malignancy. 
 
 
 
Table 5. Sensitivity Analysis Disease-Free Survival by Independent Review Committee with 
Considerations for Start of New Anti-Tumor Therapy as Events 
Censoring Rules: 
 
Date of event*/ censoring 
Censoring 
No IRC 
confirmed 
recurrence or 
occurrence of 
secondary 
malignancy or 
death 
Post baseline assessments 
performed, subject did not 
start a new anti-tumor 
therapy 
Date of last IRC reviewed scan.  Yes 
Post baseline assessments 
performed, subject did start 
a new anti-tumor therapy
Date of start of anti-tumor 
therapy. 
No 
No post baseline 
assessments performed
Date of randomization 
Yes 
IRC confirmed 
recurrence or 
secondary 
Baseline scan shows 
presence of disease 
Date of randomization 
No 
Subject did not start a new 
Date of IRC confirmed 
No 


 
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malignancy or 
death 
anti-tumor therapy (Subject 
did not have two or more 
consecutively missed/not 
readable IRC reviewed scans 
immediately prior to 
recurrence, secondary 
malignancy or death)**
recurrence or occurrence of 
secondary malignancy or death, 
whichever occurred first 
Subject did not start a new 
anti-tumor therapy (Subject 
had two or more 
consecutively missed/not 
readable IRC reviewed scans 
immediately prior to 
recurrence, secondary 
malignancy or death)**
Date of last IRC reviewed scan 
before two consecutively 
missed/not readable IRC 
reviewed scans** 
Yes 
Subject did start a new anti-
tumor therapy before IRC 
confirmed recurrence or 
secondary malignancy or 
death (Subject did not have 
two or more consecutively 
missed/not readable IRC 
reviewed scans immediately 
prior to recurrence, 
secondary malignancy or 
death or immediately prior 
to new anti-tumor therapy**
Date of start of new anti-tumor 
therapy 
No 
Subject did start a new anti-
tumor therapy before IRC 
confirmed recurrence or 
secondary malignancy or 
death (Subject had two or 
more consecutively 
missed/not readable IRC 
reviewed scans immediately 
prior to new anti-tumor 
therapy)** 
Date of last IRC reviewed scan 
before two consecutively 
missed/not readable IRC 
reviewed scans ** 
Yes 
* Note: For subjects for whom there is site confirmation of recurrence or occurrence of secondary 
malignancy in the absence of IRC imaging confirmation, the date of IRC confirmation from histo-
/cytopathology specimens will be selected as the date of event if available. For subjects for whom the IRC 
sees a finding on a scan that requires confirmation but an additional scan is not provided, if there is a 
subsequent pathology report available the pathology report could be the confirmation of the disease seen 
on the scan.  In this case the scan date should be used as the date of recurrence or secondary malignancy. 
 
**Additional details regarding the definition of two or more consecutively missed or inadequate scans 
can be found in Appendix B. For subjects who died prior to missing two scheduled assessments, they will 
be coded as an event at the date of death and will not be censored. 


 
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Table 6. Disease-Free Survival by Independent Review Committee Censoring Only at Scheduled 
Visits 
Censoring Rules: 
 
Date of event*/ censoring 
Censoring 
No IRC 
confirmed 
recurrence or 
occurrence of 
secondary 
malignancy  
Post baseline assessments 
performed 
Date of last scheduled IRC 
reviewed scan prior to 
receiving anti-tumor if 
applicable
Yes 
No post baseline 
assessments performed
Date of randomization 
Yes 
IRC confirmed 
recurrence or 
secondary 
malignancy or 
death 
Baseline scan shows 
presence of disease 
Date of randomization 
No 
Further anti-tumor therapy 
received after randomization 
and before recurrence or 
occurrence of secondary 
malignancy or death 
(Subject did not have two or 
more consecutively 
missed/not readable IRC 
reviewed scans)
Date of last scheduled IRC 
reviewed scan prior to 
receiving anti-tumor therapy 
Yes 
Further anti-tumor therapy 
received after randomization 
and before recurrence or 
occurrence of secondary 
malignancy or death 
(Subject did have two or 
more consecutively 
missed/not readable IRC 
reviewed scans)
Date of last scheduled IRC 
reviewed scan prior to 
receiving anti-tumor therapy 
and before two consecutively 
missed/not readable IRC 
reviewed scans 
Yes 
No anti-tumor therapy 
received after randomization 
(Subject did not have two or 
more consecutively 
missed/not readable IRC 
reviewed scans)
Date of scheduled IRC 
assessment which confirmed 
recurrence or occurrence of 
secondary malignancy. If event 
is death then the date of death 
will be used.
No 
No anti-tumor therapy 
received after randomization 
(Subject did have two or 
more consecutively 
missed/not readable IRC 
reviewed scans)
Date of last scheduled scan 
before two consecutively 
missed/not readable IRC 
reviewed scans 
Yes 
*Events that occur within +/-4 weeks of a scheduled scan will be considered an event at the scheduled 
scan. Events outside the 4-week window will be counted as events at the next scheduled scan time and 


 
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censoring outside the 4-week window would be censored at the previous scan.  
 
 
Table 7. Disease-Free Survival by Independent Review Committee Using a Parametric  
Model for Interval-Censored Data 
Censoring Rules: 
 
Date of event*/ censoring 
Censoring 
No IRC 
confirmed 
recurrence or 
occurrence of 
secondary 
malignancy  
Post baseline assessments 
performed 
Date of last IRC reviewed scan 
prior to receiving anti-tumor 
therapy if applicable
Yes 
No post baseline 
assessments performed 
Date of randomization 
Yes 
IRC confirmed 
recurrence or 
secondary 
malignancy or 
death 
Baseline scan shows 
presence of disease 
Date of randomization 
No 
Further anti-tumor therapy 
received after randomization 
and before recurrence or 
occurrence of secondary 
malignancy or death 
(Subject did have two or 
more consecutively 
missed/not readable IRC 
reviewed scans)
Date of midpoint between last 
IRC reviewed scan prior to 
receiving anti-tumor therapy 
and before two consecutively 
missed/not readable IRC 
reviewed scans and date of IRC 
confirmed recurrence or 
secondary malignancy or death 
Yes 
No anti-tumor therapy 
received after randomization 
(Subject did have two or 
more consecutively 
missed/not readable IRC 
reviewed scans) 
Date of midpoint between last 
IRC reviewed scan prior to two 
consecutively missed/not 
readable scans where there was 
no IRC confirmed recurrence 
and date of IRC confirmed 
recurrence or occurrence of 
secondary malignancy or death 
Yes 
 
Further anti-tumor therapy 
received after randomization 
and before recurrence or 
occurrence of secondary 
malignancy or death 
(Subject did not have two or 
more consecutively 
missed/not readable IRC 
reviewed scans)
Date of midpoint between last 
IRC reviewed scan prior to 
receiving anti-tumor therapy 
and date of IRC confirmed 
recurrence, occurrence of 
secondary malignancy or death 
Yes 
No anti-tumor therapy 
received after randomization 
(Subject did not have two or 
more consecutively 
missed/not readable IRC 
reviewed scans)
Date of IRC confirmed 
recurrence or occurrence of 
secondary malignancy or death 
No 


 
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10. 
Appendix B 
 
Data Handling for DFS Events That Occurred after Two or More Consecutively Missed or  
Not Readable Scans 
 
Section 5.1 of the SAP states the following: “For subjects who had two or more consecutively missed or 
not readable IRC reviewed scans immediately prior to a recurrence or occurrence of a secondary 
malignancy or death,  
• 
DFS will be censored on the date of the last IRC reviewed scan prior to the 
consecutively missed or not readable IRC reviewed scans.” 
 
Subjects in this trial are being followed for recurrence or occurrence of a secondary malignancy every 16 
weeks during the first 3 years of treatment after randomization and every 6 months after the first 3 years 
of treatment. Since the frequency of tumor scans varies depending on whether the tumor scan is within 3 
years from randomization or after 3 years from randomization, the length of time interval for two 
consecutively missed tumor scans can be different. 
 
There are 3 scenarios to determine whether a DFS event should be censored due to 2 or more 
consecutively missed tumor scans.  In order to simplify the description of the 3 scenarios, the following 
abbreviations are defined: 
 
Definition 
Abbreviation 
date of the last evaluable scan prior to the DFS 
event 
last-non-missing-date 
date for the first missed tumor scan that is after 
the last non-missing tumor scan prior to the DFS 
event 
1st -missed-date 
date for the 2nd consecutively missed tumor scan 
that is after the last non-missing tumor scan prior 
to the DFS event 
2nd - missed date 
date of 3 years after randomization date
3-Year (YR) rand date
 
 
(1) The last-non-missing-date is 16 weeks or more before the 3-YR rand date. 
 
                                                        16 wks                    16 wks     
 
 
 
 
Rand Date 
 
last-non 
             1st-           3-YR          2nd-                               Event 
 
 
                 missing-date          missed-    rand             missed- 
             Date 
 
 
 
                              date          date             date 
 
In Scenario (1), the targeted date for the 1st-missed-date is 16 weeks after the last-non-missing-date, 


 
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and the targeted date for the 2nd-missed-date is 32 weeks after the last non-missing-date.  After 
adding a 2-week window, the decision rule is: if the DFS event is >34 weeks after the last-non-
missing date, DFS time will be censored at the date of the last non-missing tumor scan prior to the 
DFS event, otherwise DFS time will be the non-censored time interval from randomization date to 
the date of DFS event. 
 
 
 
 
 
 
(2) The last-non-missing-date is before the 3-YR rand date, but the last-non-missing-date plus 16 
weeks is beyond the 3-YR rand date. 
 
 
 
 
 
 
 
 
 
 
 
 
                                                                          16 wks                         26 weeks      
 
              
 
 
Rand Date 
 
     last-non             3-YR           1st-                                           2nd-                                Event 
 
 
                 missing-date           rand             missed- 
                           missed-                           Date 
 
 
 
                               date              date 
                           date 
 
 
 
 
In Scenario (2), the targeted date for the 1st-missed-date is 16 weeks after the last-non-missing-date, 
and the targeted date for the 2nd-missed-date is 16 weeks plus 26 weeks after the last-non-missing-
date.  After adding a 2-week window, the decision rule is: if the DFS event is >44 weeks) after the 
last-non-missing-date, DFS time will be censored at the date of the last non-missing tumor scan prior 
to the DFS event, otherwise DFS time will be the non-censored time interval from the randomization 
date to the date of DFS event. 
 
(3) The last-non-missing-date is beyond the 3-YR rand date. 
 
 
 


 
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                                                                                        26 weeks                26 weeks  
 
              
 
 
Rand Date 
 
      3-YR                  last-non-                    1st-                            2nd-                              Event 
 
 
                        rand date            missing date             missed- 
          missed-                         Date 
 
 
 
                                                                  date 
          date 
 
 
In Scenario (3), the targeted date for the 1st- missed-date is 26 weeks after the last-non-missing-date, 
and the targeted date for the 2nd-missed-date is 52 weeks after the last-non-missing-date.  After 
adding a 4-week window, the decision rule is: if the DFS event is >56 weeks after the last non-
missing-date, DFS time will be censored at the date of the last non-missing tumor scan prior to the 
DFS event, otherwise DFS time will be the non-censored time interval from randomization to the 
date of DFS.   
 
If no DFS event occurred after the 2 or more consecutively missed tumor scans, DFS time will be the 
censored time interval from randomization date to the last tumor scan date regardless whether these 
scans were done after 2 or more consecutively missed tumor scans. 
 
11. 
Table Shells and Specifications 
 
 
11.1. Table Shells 
 
Table shells are provided in a separate document. 
 
12. 
Figure Shells and Specifications 
 
 
12.1. Figure Shells 
 
Listing shells are provided in a separate document. 
 
 
13. 
Listing Shells and Specifications 
 
 
13.1. Listing Shells 
 
Listing shells are provided in a separate document. 
 
 
14. 
Programming Conventions for Outputs: 


 
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Partial dates should be presented as   - -NOV1999 or - - - - - 1999 as needed. 
 
Partial times should be presented as --:30 or 14:-- as needed. 
 
Listings should be sorted according to the order of the columns.