Conditions: Carcinoma, Renal Cell
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 350
Healthy volunteers: no

Brief summary:
This is a Phase 3, open-label, randomized, controlled, multi-national, multi-center, parallel-arm study comparing tivozanib to sorafenib in participants with refractory advanced renal cell carcinoma (RCC).

Participants will be randomized (1:1) to treatment with tivozanib or sorafenib.

Participants will be stratified by International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk category (favorable; intermediate; poor) and prior therapy (two prior vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR TKI); a prior checkpoint inhibitor \[programmed cell death -1 protein (PD-1) or PD-1 ligand (PD1-L) inhibitor\] plus a prior VEGFR TKI; a prior VEGFR TKI plus any other systemic agent).

All participants will be evaluated for progression free survival, overall survival, objective response rate, and the duration of response as well as safety and tolerability.

Pharmacokinetic (PK) analyses are also included in study.

Detailed description:

Arms:
arm 1: Participants randomized to this arm will receive the study drug, tivozanib hydrochloride. arm 2: Participants randomized to this arm will receive the comparator drug, sorafenib.

Interventions: intervention 1: Tivozanib hydrochloride intervention 2: Sorafenib
Intervention descriptions: intervention 1: Tivozanib hydrochloride intervention 2: Sorafenib

Protocol document:
Prot_000.pdf: 
 
A Phase 3, Randomized, Controlled, Multi-Center, Open-Label Study to Compare 
Tivozanib Hydrochloride to Sorafenib in Subjects With Refractory Advanced Renal Cell 
Carcinoma  
PROTOCOL:  AV-951-15-303 
IND Number:  75,547 
EUDRACT Number:  2015-003607-30 
AVEO PHARMACEUTICALS, INC. 
1 Broadway 
Cambridge, MA USA 02142 
Tel:  (617) 531-8292 
Fax:  (617) 902-2577 
www.aveooncology.com 
________________________________________ 
AVEO Pharma Limited 
59-60 Thames Street 
Windsor, UK, SL4 1TX 
Version 
Country(ies) 
Date 
1.0 
Global 
26-Aug-2015 (not distributed) 
2.0 
Global 
01-Oct-2015 
2.1 
France 
19-Jan-2016 
2.2 
UK 
20-Jan-2016 
3.0 
Global 
06-Jul-2016 
3.1 
France 
20-Jul-2016 
3.2 
UK 
20-Jul-2016 
4.0 
Global 
01-Oct-2018 
 
 
CONFIDENTIAL AND PROPRIETARY 
This document is the confidential property of AVEO Pharmaceuticals, Inc. (the sponsor), and is intended solely for the guidance of this 
clinical investigation.  The information contained herein may not be disclosed to parties not associated with this clinical investigation 
without the written authorization of the sponsor.  No part of this document may be reproduced, referenced, stored in a retrieval system, or 
transmitted, in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without the written 
authorization of the sponsor.  The foregoing shall not apply to disclosure required by applicable laws or governmental regulations; 


Protocol: AV-951-15-303 
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Page 2 of 111 
 
Confidential Property of AVEO Pharmaceuticals, Inc. 
however, you will give notice to the sponsor of any such disclosure as soon as practicable. 


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Confidential Property of AVEO Pharmaceuticals, Inc. 
PROCEDURES IN CASE OF EMERGENCY 
Emergency Contact Information 
Chief Medical Officer: 
Name:  Michael N Needle, MD
Aveo Oncology 
1 Broadway, 14th Floor 
Cambridge, MA  02142 
Mobile:  (303) 524-0376 
mneedle@aveooncology.com
PAREXEL Medical Monitor: 
Name:  Gamal Elsawah, MD 
PAREXEL International 
2 Federal Street 
Billerica  MA 01821 
Phone:  (610) 721-2255 
Gamal.Elsawah@PAREXEL.com 
For urgent medical study questions, please contact the AVEO Chief Medical Officer or PAREXEL Medical Monitor. 
After business hours, weekends, and on holidays, please send an email message and a response will be placed. 


Protocol: AV-951-15-303 
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PROTOCOL SIGNATURE PAGE 
Declaration of Sponsor or Responsible Medical Officer 
This study protocol was subjected to critical review. The information it contains is consistent 
with current knowledge of the risks and benefits of the investigational product, as well as with 
the moral, ethical, and scientific principles governing clinical research as set out in the 
Declaration of Helsinki and the guidelines on Good Clinical Practice. 
Michael Needle, MD 
Chief Medical Officer 
A VEO Pharmaceuticals, Inc. 
Investigator Signature 
I 
Date of Signature 
(dd-nunm-yyyy) 
I have read this protocol and agree that it contains all necessary details for carrying out the study 
as described. I will conduct this protocol as outlined therein, including all statements regarding 
confidentiality. I will make a reasonable effort to complete the study within the time designated. 
I will provide copies of the protocol and access to all information furnished by the sponsor to 
study personnel under my supervision. I will discuss this material with them to ensure that they 
are fully informed of the study requirements and procedures. I understand that the study may be 
terminated or enrollment suspended at any time by the sponsor, with or without cause, or by me 
if it becomes necessary to protect the best interests of the study subjects. 
I agree to conduct this study in full accordance with all applicable regulations and Good Clinical 
Practice (GCP). 
Investigator's Signature 
Investigator's Name (print) 
Page 3 of109 
Date of Signature 
(dd-mnun-yyyy) 
Confidential Property of A VEO Pharmaceuticals, Inc. 


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1
SYNOPSIS 
Name of sponsor/company:  AVEO Pharmaceuticals, Inc. 
Name of investigational product:  Tivozanib Hydrochloride (AV-951) capsules 
Title of study:  A Phase 3, Randomized, Controlled, Multi-Center, Open-Label Study to Compare Tivozanib 
Hydrochloride to Sorafenib in Subjects With Refractory Advanced Renal Cell Carcinoma 
Study Number:  AV-951-15-303 
Estimated number of study center(s):  Approximately 160-190 centers 
Study duration (years):  
Estimated date first subject enrolled:  June 2016 
Estimated date last subject enrolled:  August 2017 
Established data cut-off date: 04 October 2018
Phase of development:  
3 
Objectives: 
Primary: 
•
To compare the progression-free survival (PFS) of subjects with refractory advanced renal cell carcinoma 
(RCC) randomized to treatment with tivozanib hydrochloride (tivozanib) or sorafenib as assessed by 
blinded independent radiological review (IRR) of computerized tomography (CT) or magnetic resonance 
imaging (MRI). 
Secondary: 
•
To compare the overall survival (OS) of subjects randomized to treatment with tivozanib or sorafenib 
•
To compare objective response rate (ORR) and duration of response (DoR) of subjects randomized to 
treatment with tivozanib or sorafenib 
•
To compare the safety and tolerability of tivozanib and sorafenib. 
Tertiary: 
•
To explore any relationship between:
-
 tivozanib and sorafenib drug levels and activity
-
tivozanib and sorafenib drug levels and adverse events (AEs)
Methodology:  Open-label, randomized, controlled, multi-national, multi-center, parallel-arm study. 
Subjects will be randomized in a 1:1 ratio (tivozanib: sorafenib) stratified by the International Metastatic Renal Cell 
Carcinoma Database Consortium (IMDC) risk category (favorable; intermediate; poor) and prior therapy (two prior 
vascular endothelial growth factor [VEGF] receptor tyrosine kinase inhibitors [VEGFR TKIs]; a prior checkpoint 


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Name of sponsor/company:  AVEO Pharmaceuticals, Inc. 
Name of investigational product:  Tivozanib Hydrochloride (AV-951) capsules 
inhibitor [programmed cell death -1 protein (PD-1) or PD-1 ligand (PD1-L) inhibitor] plus a prior VEGFR TKI; a 
prior VEGFR TKI plus any other systemic agent).  Once the strata have been identified, treatment will be randomly 
assigned to a subject within the strata using a complete permuted block design, in an unblinded fashion (open–label). 
In the event a subject had both 2 TKIs and a checkpoint inhibitor, the subject will be stratified according to the most 
recent line of therapy.  
Subjects must begin treatment with study drug within 14 days after randomization.  
Number of subjects (planned):  Approximately 322 subjects will be enrolled (161 per treatment arm)
Diagnosis and main criteria for inclusion:  
Subjects may be male or female, and must meet the following criteria to be included:
1.
≥ 18-years of age.  
2.
Subjects with metastatic RCC who have failed 2 or 3 prior systemic regimens, one of which includes a 
VEGFR TKI other than sorafenib or tivozanib. 
a. Postoperative or adjuvant systemic therapy will not be counted as a prior therapy unless recurrence is 
detected within 6 months of completion of treatment, in which case it will be counted as a prior 
therapy for metastatic disease. 
b. Subjects must be off all systemic anti-cancer therapy or radiotherapy for at least 2 weeks prior to 
Cycle 1 Day 1. 
3.
Subjects must have recovered from the AEs of prior therapy or returned to baseline. Controlled AEs such 
as hypothyroidism or hypertension are permitted. 
4.
Histologically or cytologically confirmed RCC with a clear cell component (subjects with pure papillary 
cell tumor or other non-clear cell histologies, including collecting duct, medullary, chromophobe, and 
unclassified RCC are excluded). 
5.
Measurable disease per the Response Evaluation Criteria in Solid Tumors (RECIST) criteria Version 1.1.   
6.
Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.  
7.
Life expectancy ≥ 3 months.  
8.
If female and of childbearing potential, documentation of negative pregnancy test prior to enrollment.   
9.
Ability to give written informed consent and comply with protocol requirements.   
10.
Sexually active pre-menopausal female subjects (and female partners of male subjects) must use adequate 
contraceptive measures, while on study and for at least 90 days after the last dose of study drug.  Sexually 
active male subjects must use adequate contraceptive measures, while on study and for at least 90 days 
after the last dose of study drug.  All fertile male and female subjects and their partners must agree to use a 


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Confidential Property of AVEO Pharmaceuticals, Inc. 
Name of sponsor/company:  AVEO Pharmaceuticals, Inc. 
Name of investigational product:  Tivozanib Hydrochloride (AV-951) capsules 
highly effective method of contraception.  Effective birth control includes (a) intrauterine device (IUD) 
plus one barrier method; or (b) 2 barrier methods.  Effective barrier methods are male or female condoms, 
diaphragms, and spermicides (creams or gels that contain a chemical to kill sperm).  (Note:  Oral, 
implantable, or injectable contraceptives may be affected by cytochrome P450 interactions, and are not 
considered effective for female subjects in this study)   
Subjects to be excluded  
1.
Prior treatment with sorafenib or tivozanib. 
2.
More than 3 prior regimens for metastatic RCC. 
3.
Known central nervous system (CNS) metastases other than stable, treated brain metastases. Subjects with 
previously treated brain metastasis will be allowed if the brain metastasis has been stable by neuroimaging 
without steroid treatment for at least 3 months following prior treatment (radiotherapy or surgery). 
4.
Any of the following hematologic abnormalities:  
•
Hemoglobin < 9.0 g/dL (packed red blood cell transfusion is permitted) 
•
Absolute neutrophil count (ANC) < 1500 per mm3
•
Platelet count < 100,000 per mm3
5.
Any of the following serum chemistry abnormalities: 
•
Total bilirubin > 1.5 × upper limit of normal (ULN) (or > 2.5 × ULN for subjects with Gilbert’s 
syndrome) 
•
Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 2.5 × ULN (or > 5 × ULN for 
subjects with liver metastasis) 
•
Alkaline phosphatase > 2.5 × ULN (or > 5 × ULN for subjects with liver or bone metastasis) 
•
Creatinine > 1.5 × ULN unless creatinine clearance > 40 mL/min. Creatinine clearance can be 
calculated by standard equations (e.g. Cockroft-Gault) or measured. 
6.
Significant cardiovascular disease, including: 
•
Active clinically symptomatic left ventricular failure 
•
Uncontrolled hypertension:  Systolic blood pressure > 150 mmHg or diastolic blood pressure 
> 100 mmHg on 2 or more antihypertensive medications, documented on 2 consecutive measurements 
taken at least 2 hours apart 
•
Myocardial infarction, severe angina, or unstable angina within 6 months prior to administration of 
first dose of study drug 
•
History of serious ventricular arrhythmia (ie, ventricular tachycardia or ventricular fibrillation) 


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Name of sponsor/company:  AVEO Pharmaceuticals, Inc. 
Name of investigational product:  Tivozanib Hydrochloride (AV-951) capsules 
•
Cardiac arrhythmias requiring anti-arrhythmic medications (except for atrial fibrillation that is well 
controlled with anti-arrhythmic medication) 
7.
Non-healing wound, bone fracture, or skin ulcer. 
8.
Active peptic ulcer disease, inflammatory bowel disease, ulcerative colitis, or other gastrointestinal 
condition with increased risk of perforation; history of abdominal fistula, gastrointestinal perforation, or 
intra-abdominal abscess within 4 weeks prior to administration of first dose of study drug. 
9.
Serious/active infection or infection requiring parenteral antibiotics. 
10.
Inadequate recovery from any prior surgical procedure or major surgical procedure within 4 weeks prior to 
administration of first dose of study drug. 
11.
Significant thromboembolic or vascular disorders within 6 months prior to administration of first dose of 
study drug, including but not limited to:   
•
Symptomatic Pulmonary embolism 
•
Cerebrovascular accident (CVA) or transient ischemic attack (TIA) 
•
Peripheral arterial ischemia > Grade 2 
•
Coronary or peripheral artery bypass graft  
12.
Significant bleeding disorders within 6 months prior to administration of first dose of study drug, including 
but not limited to:   
•
Hematemesis, hematochezia, melena or other gastrointestinal bleeding ≥ Grade 2 
•
Hemoptysis or other pulmonary bleeding ≥ Grade 2 
•
Hematuria or other genitourinary bleeding ≥ Grade 2 
13.
Currently active second primary malignancy, including hematologic malignancies (leukemia, lymphoma, 
multiple myeloma, etc.), other than non-melanoma skin cancers, non-muscle-invasive urothelial cancer, 
non-metastatic prostate cancer, in situ cervical cancer and ductal or lobular carcinoma in situ of the breast. 
Subjects are not considered to have a currently active malignancy if they have completed anti-cancer 
therapy and have been disease free for >2 years.  
14.
Pregnant or lactating females.  
15.
History of genetic or acquired immune suppression disease such as human immunodeficiency virus (HIV), 
subjects on immune suppressive therapy for organ transplant. 
16.
Life-threatening illness or organ system dysfunction compromising safety evaluation.  
17.
Requirement for hemodialysis or peritoneal dialysis. 
18.
Inability to swallow pills, malabsorption syndrome or gastrointestinal disease that severely affects the 


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absorption of tivozanib or sorafenib, major resection of the stomach or small bowel, or gastric bypass 
procedure. 
19.
Psychiatric disorder or altered mental status precluding informed consent or necessary testing. 
20.
Participation in another interventional protocol. 
Drugs and treatments to be excluded  
The following medications/treatments are prohibited during the study:   
1.
Chemotherapy, biological therapy (including cytokines, signal transduction inhibitors, monoclonal 
antibodies), immunotherapy or any other therapy for RCC. 
2.
Systemic hormonal therapy, with the exception of:  
•
Hormonal therapy for appetite stimulation or contraception 
•
Nasal, ophthalmic, inhaled and topical steroid preparations 
•
Androgen suppression therapy for non-metastatic prostate carcinoma 
•
Hormone replacement therapy for conditions such as adrenal insufficiency, hypothyroidism, etc. 
•
Low-dose maintenance steroid therapy (equivalent of prednisone ≤ 10 mg/day) for other conditions 
3.
Treatment with radiotherapy. 
4.
Herbal preparations/supplements (including daily multivitamin/mineral supplement containing herbal 
components) or topical ointments containing herbal components. 
5.
Treatment with strong cytochrome P450 (CYP3A4) inducers or inhibitors (see Appendix C). 
6.
Treatment with full dose oral anticoagulants such as warfarin, acenocoumarol, fenprocoumon, or similar 
agents unless they have been on a stable dose for more than 2 weeks prior to enrollment.  Full dose 
anticoagulation with low molecular weight heparin or unfractionated heparin administered subcutaneously 
is allowed. 
Investigational product, dosage and mode of administration:  
Tivozanib:  1.5 mg orally once daily.   
Subjects will receive 1.5 mg tivozanib once daily beginning on Day 1 for 21 days followed by 7 days off treatment.  
One cycle will be defined as 4 weeks in duration, consisting of 3 weeks on treatment and a week off treatment.  
Cycles will be repeated every 4 weeks. 


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Name of sponsor/company:  AVEO Pharmaceuticals, Inc. 
Name of investigational product:  Tivozanib Hydrochloride (AV-951) capsules 
Reference therapy, dosage and mode of administration:
Sorafenib:  400 mg orally twice daily  
Subjects will receive 400 mg sorafenib twice daily continuously, beginning on Day 1.  One cycle will be defined as 
4 weeks of treatment.  Cycles will be repeated every 4 weeks.  
Dose reduction: 
Tivozanib:  Dose reduction will be allowed for subjects with ≥ Grade 3 drug-related adverse events.  The exception 
is hypertension, which must be treated with anti-hypertensive drugs prior to dose reduction.   
The dose of tivozanib may be reduced to 1.0 mg/day.  If a subject is unable to tolerate a dose of 1.0 mg/day due to 
toxicities thought to be related to tivozanib, treatment should be interrupted for up to 4 weeks.  Once the dose of 
tivozanib is reduced, it may not be re-escalated throughout the study.   
Sorafenib:  Dose reduction will be allowed for subjects with ≥ Grade 3 drug-related adverse events.  The dose of 
sorafenib will be reduced to 400 mg once daily.  If toxicities do not resolve, sorafenib may be further reduced to 
400 mg once every other day.  If a subject is unable to tolerate a dose of 400 mg once every other day due to 
toxicities thought to be related to sorafenib, treatment should be interrupted.  If toxicities resolve to ≤ Grade 1, the 
dose of sorafenib may be re-escalated to the previous dose level at the discretion of the investigator. 
Dose interruption (tivozanib and/or sorafenib): 
   
Subjects with Grade 4 drug-related toxicity, or Grade 3 drug-related toxicity that is persistent despite dose reduction 
and appropriate medical care, should have their treatment interrupted to allow for adequate resolution of the toxicity.  
Tivozanib/sorafenib may be interrupted for up to 4 weeks.  If a subject is able to resume treatment after interruption 
of ≤ 4 weeks, missed doses will not be made up (ie, cycle duration will remain unchanged).  If any drug-related 
toxicity results in interruption of > 4 weeks, the subject should be discontinued from the study unless there is clear 
benefit from treatment, in which case the investigator must contact the medical monitor to review the subject’s 
condition in order to resume treatment.  Subjects removed from treatment for reasons other than radiological 
evidence of progressive disease should still be followed with regular tumor assessments until disease progression is 
confirmed by an independent radiology review or start of new treatment, and for survival thereafter.   
Criteria for evaluation: 
Safety:   
NCI Common Terminology Criteria for Adverse Events (CTCAE Version 4.03) will be used for grading toxicities.  
Subjects will be monitored throughout the treatment and 30-day follow-up period for occurrence of adverse events 
(AEs; acute, delayed, and/or cumulative), as well as for changes in clinical status, vital sign measurements, and 
laboratory data.  
Safety parameters to be measured / assessed include eligibility assessment, medical history, vital sign measurements, 


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physical examination, hematology, serum chemistries, thyroid function tests, coagulation parameters, urinalysis, 
pregnancy test, ECOG performance status, and electrocardiogram (ECG).   
Disease status:   
Data on the duration of disease stabilization or any objective response, as well as the time to disease progression will 
be collected for all subjects.  Disease parameters to be assessed: 
•
Disease classification (histological/cytological type and stage of carcinoma) 
•
Diagnostic imaging with measurement of target lesions performed by an independent review 
committee 
•
Response assessment using RECIST (Version 1.1) criteria 
•
Radiology studies (CT scan or MRI) will be performed every 8 weeks following Cycle 1, Day 1 for 
assessing disease status 
Duration of treatment:    
Subjects with documented stable disease or an objective response may continue to receive therapy at the same dose 
and schedule until progression as long as tolerability is acceptable.   
Discontinuation:   
Subjects experiencing unacceptable toxicities will be discontinued from further study treatment.  Subjects with 
radiological evidence of progressive disease per investigator/local radiology assessment should continue treatment 
until progressive disease is verified by an independent radiologist.  Images should be submitted for independent 
review as soon as possible (see Imaging Manual for specific instructions).  Verification is not required in the 
following circumstance: 
•
Significant clinical deterioration that is indicative of progressive disease 
Subjects who have documented disease progression will be discontinued from the study treatment.   
Follow-up:   
Each subject will be followed until death from any cause (unless the subject is lost to follow-up, withdraws consent 
for the entire study, or the Sponsor terminates the study early). Once discontinued from study drug treatment, all 
subjects are to be followed for evidence of new onset of adverse events, and to ensure resolution or stabilization of 
existing ongoing adverse events, for 30 days from the last dose of study drug.  After the 30-Day Follow-up Visit, 
subjects will be contacted by the site once every 3 months to collect long-term survival data.   
Statistical methods:   
A sample size of 322 subjects (161 subjects per treatment arm) with total number of 255 events will provide 90% 
power to detect a statistically significant difference between treatment arms with respect to PFS as assessed by an 


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Name of sponsor/company:  AVEO Pharmaceuticals, Inc. 
Name of investigational product:  Tivozanib Hydrochloride (AV-951) capsules 
IRR.  The sample size was determined based on the following assumptions: 
•
The distribution of the PFS for the 2 treatment arms will be compared by using a Log-rank test with a 
two-sided 5% significance level (α) 
•
The median PFS for subjects receiving sorafenib and tivozanib is 4 months and 6 months, respectively, 
(an increase of 2 months or 50%) 
•
Equal numbers of subjects will be assigned to each treatment arm 
•
Enrollment will take 15 months 
•
The drop out percentage per treatment arm will be 3% 
Data will be summarized using descriptive statistics (number of subjects, mean, median, standard deviation, 
minimum, and maximum) for continuous variables and using frequency and percentages for discrete variables.   
The primary analysis will compare the distribution of the PFS between the two treatment arms by using the stratified 
Log-rank test, in which the stratification factors are IMDC risk category (favorable; intermediate; poor) and prior 
therapy (two prior VEGF TKIs; a prior checkpoint inhibitor [PD-1 or PD1-L inhibitor] plus a prior VEGFR TKI; a 
prior VEGFR TKI plus any other systemic agent).  PFS will be based on the CT or MRI scan assessed by the IRR.  
PFS graphs will be presented by treatment arm. 
The first secondary analysis will compare OS between the 2 treatment arms by using the stratified Log-rank test, the 
stratification factors included in the primary analysis, and two-sided 0.8% significance level (utilizing a Lan-DeMets 
alpha spending function with an O’Brien-Fleming boundary).  An interim OS analysis will be done at the time of the 
final PFS analysis.  It is expected that 149 OS events would have occurred at the time of final PFS analysis. 
An interim analysis will be performed after 128 PFS events have been observed.  The interim analysis will look into 
the study’s futility using PFS as the efficacy evaluation endpoint.  This will utilize a Lan-DeMets error spending-
type function with an O’Brien-Fleming stopping boundary with an estimated two-sided beta (Type II error) of 1.2 % 
spent during this interim look.  The interim analysis will be performed by an independent statistician.  The 
independent statistician will evaluate and interpret the results of the interim analysis and will provide corresponding 
recommendation whether to stop the study for futility or for the study to continue until end of study condition has 
been met. 
Two populations will be defined for the efficacy analysis:  Intent-to-treat (ITT; defined as all subjects who were 
randomized into the study) and per protocol (PP; defined as all subjects in the ITT population who did not have 
major protocol deviations, have received at least two cycles (8 weeks) of protocol treatment, and met all eligibility 
criteria).  Primary efficacy analysis will be based on ITT where subjects will be analyzed as randomized. 
The safety population (SAF) will include all subjects who received at least one dose of either study drug.  Subjects 
will be analyzed as treated. 


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Name of sponsor/company:  AVEO Pharmaceuticals, Inc. 
Name of investigational product:  Tivozanib Hydrochloride (AV-951) capsules 
Safety observations and measurements, including study drug exposure, adverse events, laboratory data, concomitant 
medications, physical examination, vital signs, ECG, and health outcome measurements, will be summarized and 
presented in tables and listings using the SAF population.   


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Confidential Property of AVEO Pharmaceuticals, Inc. 
Table 1: 
Study Design and Schedule of Assessments 
STUDY PROCEDURES
SCREEN 
CYCLE 1 
CYCLE 2 
SUBSEQUENT 
CYCLES 
END OF 
TREATMENT 
(up to 7 days 
after last dose)r
30-DAY 
FOLLOW-
UP 
(±7 days)  
UNSCHED
-ULEDs
LONG TERM 
RESPONSE & 
SURVIVAL 
FOLLOW-UP 
Cycle Day 
-21 to -1
1 
15 
± 2 daysp
1 
± 2 daysp
1 
± 2 daysp
CONSENT AND MEDICAL HISTORY
Informed Consenta
X 
Medical & Disease History 
X 
IMDC Risk Category 
X 
SAFETY ASSESSMENTS 
Concomitant Medications  
X 
To be collected from the date informed consent form signed to 30 days after last dose of study drug 
Adverse Event Assessments 
X 
To be collected from the date informed consent form signed to 30 days after last dose of study drug 
Study Drug Administration 
Daily x 3 or  
4 weeksq
Daily x 3 or 
4 weeksq
Daily x 3 or 
4 weeksq
ECOG Performance Status  
X 
Xi
X 
X 
X 
X 
X 
X 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Examinationb
X 
Xi
X 
X 
X 
X 
X 
X 
Hematologyc
X 
Xi
X 
X 
X 
X 
X 
X 
Serum Chemistriesd
X 
Xi
X 
X 
X 
X 
X 
X 
Coagulation Parameterse
X 
Xi
X 
X 
X 
X 
X 
X 
Thyroid Function Testsf
X 
X 
Xg
X 
X 
X 
Urinalysis with 
Microscopich
X 
Xi
X 
X 
X 
X 
X 
X 
Pregnancy Testj
X 
X 
X 


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Table 1: 
Study Design and Schedule of Assessments 
STUDY PROCEDURES
SCREEN 
CYCLE 1 
CYCLE 2 
SUBSEQUENT 
CYCLES 
END OF 
TREATMENT 
(up to 7 days 
after last dose)r
30-DAY 
FOLLOW-
UP 
(±7 days)  
UNSCHED
-ULEDs
LONG TERM 
RESPONSE & 
SURVIVAL 
FOLLOW-UP 
Cycle Day 
-21 to -1
1 
15 
± 2 daysp
1 
± 2 daysp
1 
± 2 daysp
12-Lead ECG 
X 
X 
X 
X 
Disease / Response 
Assessment (CT Scan or 
MRI Scan) 
Xk
Every 8 weeks (±3 days) from Cycle 1, Day 1 
Xl
X 
Xm
Study Drug Diary 
X 
X 
X 
X 
X 
X 
Pharmacokineticsn
X 
X 
Contact of subject by siteo
X 


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Table 1: 
Study Design and Schedule of Assessments 
STUDY PROCEDURES
SCREEN 
CYCLE 1 
CYCLE 2 
SUBSEQUENT 
CYCLES 
END OF 
TREATMENT 
(up to 7 days 
after last dose)r
30-DAY 
FOLLOW-
UP 
(±7 days)  
UNSCHED
-ULEDs
LONG TERM 
RESPONSE & 
SURVIVAL 
FOLLOW-UP 
Cycle Day 
-21 to -1
1 
15 
± 2 daysp
1 
± 2 daysp
1 
± 2 daysp
a. Informed consent may be obtained outside the 21-day window; however, consent must be obtained prior to any protocol-specific procedures being performed. 
b. Physical exams (PE):  Complete PE at screening, including height (at Screening visit only) and weight; directed PE thereafter, including weight.   
c. Hematology to include complete blood count (CBC) with differential and platelet count.   
d. Serum chemistries to include sodium, potassium, chloride, bicarbonate (optional), blood urea nitrogen (BUN), creatinine, glucose, total bilirubin, direct bilirubin, AST, ALT, lactate dehydrogenase 
(LDH), alkaline phosphatase, calcium, magnesium, phosphorous, albumin, amylase, lipase, and total protein. 
e. Coagulation parameters to include prothrombin time (PT) and/or international normalized ratio (INR), and partial thromboplastin time (PTT). 
f. Total T3 (triiodothyronine) (optional), free T4 (thyroxine), and thyroid stimulating hormone (TSH) levels.  
g. To be performed during every even-numbered cycle beyond Cycle 2 (ie, Cycle 4, 6, 8 etc.). 
h. Urinalysis to include protein, glucose, ketones, urobilinogen, occult blood, and microscopic sediment evaluation.  A 24-hour urine for protein will be performed whenever protein is 4+. 
i. Prior to Cycle 1:  Must be performed prior to 1st dose; need not be assessed again if ≤ 7 days since corresponding assessment performed at screening. 
j. Pregnancy test:  Serum β-hCG required for premenopausal, non-sterilized females.   
k. Screening CT/MRI scan may be performed up to 30 days prior to first dose as part of standard of care, and prior to signing of the informed consent if performed in compliance with the protocol 
requirements.  Screening scan to include head, chest, abdomen, and pelvis.   
l. Not needed if last scan was within 30 days prior to End-of-Treatment Visit and showed progressive disease (PD), as confirmed by independent radiology review.  
m. For subjects with stable disease or objective response at the time of treatment discontinuation, who discontinue for reasons other than radiological evidence of progressive disease, tumor assessments 
will continue to be collected (every 2 months during the first year [beginning from the date of the last scan performed prior to treatment discontinuation], every 3 months during the second year, and 
every 6 months thereafter) until disease progression is confirmed by independent radiology review or start of another therapy.  A ±3 day visit window applies to tumor assessments for subjects that have 
discontinued study drug. 
n. Two blood samples for pharmacokinetic (PK) analysis will be collected at the following time points from all subjects:  Cycle 1, Day 1- 4 hours post-dose and Cycle 1, Day 15- pre-dose (within 2 hours 
before dosing). 
o. After the 30-Day Follow-up visit, subjects will be contacted once every 3 months by the site to collect long-term survival data.  Additional contacts may be made to support key analyses, such as the 
analysis of overall survival at the time of the final PFS analysis, and the final analysis of overall survival.  A ±7 day window applies for the scheduled long term follow-up contacts. 
p. A ±2 day window applies to all visit procedures except study drug administration.   
q. The duration of treatment for tivozanib is 21 of 28 days, and for sorafenib is 28 of 28 days. 
r. All subjects will have an EOT visit when they permanently discontinue any further study treatment. The EOT visit will occur up to 7 days after the last dose of study drug. Assessments performed 
within 3 days of the EOT visit need not be repeated and may be documented as the EOT assessment (except for the response assessment which does not need to be repeated if performed within 30 days 
and showed progressive disease).  Subjects starting new anti-cancer therapy after the last dose of study drug must complete the End of Treatment Visit assessments in advance of starting the new anti-
cancer therapy. 
s. If additional visits are needed, these assessments may be obtained/ performed/ measured as clinically indicated.


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TABLE OF CONTENTS 
PROCEDURES IN CASE OF EMERGENCY ......................................................................... 2
PROTOCOL SIGNATURE PAGE ........................................................................................... 3
1
SYNOPSIS ......................................................................................................................... 4
2
LIST OF ABBREVIATIONS AND EXPANDED TERM ............................................. 20
3
INTRODUCTION ........................................................................................................... 23
3.1
Background ............................................................................................................ 23
3.2
Pharmacology ........................................................................................................ 23
3.3
Safety Pharmacology ............................................................................................. 24
3.4
Toxicology ............................................................................................................. 24
3.5
Pharmacokinetics ................................................................................................... 26
3.6
Previous Human Experience .................................................................................. 26
3.6.1
Pharmacokinetics in Subjects with Solid Tumors ....................................... 26
3.6.2
Clinical Activity ........................................................................................... 26
3.7
Study Rationale ...................................................................................................... 29
3.7.1
Rationale for the Tivozanib Dose ................................................................ 29
3.7.2
Rationale for the Tivozanib Dosing Regimen ............................................. 29
3.7.3
Rationale for the Study Design .................................................................... 29
3.7.4
Use in Pregnancy ......................................................................................... 30
3.7.5
Potential Risks/Benefits of Therapy With Sorafenib (Nexavar) .............. 30
4
STUDY OBJECTIVES AND PURPOSE ....................................................................... 31
4.1
Primary Objective .................................................................................................. 31
4.2
Secondary Objectives............................................................................................. 31
4.3
Tertiary Objectives................................................................................................. 31
5
INVESTIGATIONAL PLAN .......................................................................................... 31
5.1
Overall Study Design and Plan: Description ......................................................... 31
5.2
Approximate Duration of Study ............................................................................. 31
5.3
Approximate Number of Subjects ......................................................................... 31
5.4
Subject Enrollment................................................................................................. 32
5.4.1
Subject Enrollment Assignment .................................................................. 32
5.4.2
Treatment Randomization ............................................................................ 32
6
DIAGNOSIS AND MAIN CRITERIA ........................................................................... 32
6.1
Subject Inclusion Criteria ...................................................................................... 32
6.2
Subject Exclusion Criteria ..................................................................................... 33
6.3
Drugs and Other Treatments to be Excluded ......................................................... 35
7
TREATMENT OF SUBJECTS ....................................................................................... 36
7.1
Procedures/Parameters to be Measured ................................................................. 36


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7.1.1
Screening Visit ............................................................................................. 39
7.1.2
Cycle 1, Day 1 (Baseline) Visit ................................................................... 40
7.1.3
Cycle 1, Day 15 Visit (± 2 days) ................................................................. 40
7.1.4
Cycle 2, Day 1 Visit (± 2 days) ................................................................... 41
7.1.5
Every 8 weeks from Cycle 1, Day 1 (± 3 days) ........................................... 41
7.1.6
Subsequent Cycles – Day 1 Visit (± 2 days) ............................................... 41
7.1.7
End-of-Treatment ......................................................................................... 42
7.1.8
30-Day Follow-Up Visit (± 7 days) ............................................................. 42
7.1.9
Unscheduled Visits (To Occur as Needed) .................................................. 43
7.1.10
Long Term Response and Survival Follow-Up ........................................... 43
7.2
Study Drug Administration .................................................................................... 44
7.2.1
Tivozanib Administration ............................................................................ 44
7.2.2
Sorafenib Administration ............................................................................. 44
7.2.3
Review of Safety Data During Study .......................................................... 44
7.2.4
Duration of Study Treatment ....................................................................... 45
7.2.5
Duration of Follow-Up ................................................................................ 45
7.3
Prior and Concomitant Medications ...................................................................... 46
7.4
Randomization and Blinding ................................................................................. 46
8
STUDY DRUG MATERIALS AND MANAGEMENT ................................................ 46
8.1
Study Drug ............................................................................................................. 46
8.2
Study Drug Packaging and Labeling ..................................................................... 47
8.3
Study Drug Shipment ............................................................................................. 47
8.4
Dispensing of Study Drug and Dosing Compliance .............................................. 47
8.5
Study Drug Storage ................................................................................................ 47
8.6
Study Drug Accountability .................................................................................... 47
8.7
Study Drug Handling ............................................................................................. 47
8.7.1
Disposition of Used Supplies ....................................................................... 48
8.7.2
Inventory of Unused Supplies ...................................................................... 48
9
ASSESSMENT OF ACTIVITY ...................................................................................... 48
9.1
Disease Classification and Response Assessments................................................ 48
10
MANAGEMENT OF TOXICITY ................................................................................... 49
10.1
Grading and Recording of Toxicity ....................................................................... 49
10.2
Evaluation and Treatment of Toxicity ................................................................... 49
10.3
Management of Skin Toxicities (Sorafenib) .......................................................... 50
10.4
Study Drug Administration Modification .............................................................. 50
10.4.1
Tivozanib Dose Reduction ........................................................................... 51
10.4.2
Tivozanib Dose Interruption ........................................................................ 51
10.4.3
Sorafenib Dose Reduction ........................................................................... 52


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10.4.4
Sorafenib Dose Interruption ......................................................................... 52
11
REMOVING SUBJECTS FROM STUDY ..................................................................... 52
11.1
Criteria for Treatment Discontinuation (Stopping Rules) ..................................... 52
12
ADVERSE AND SERIOUS ADVERSE EVENTS ........................................................ 54
12.1
Definition of Adverse Events................................................................................. 54
12.1.1
Abnormal Laboratory Findings and Other Objective Measurements .......... 55
12.1.2
Medical History ........................................................................................... 55
12.1.3
Exacerbation of Primary Malignancy .......................................................... 55
12.2
Evaluating Adverse Events .................................................................................... 55
12.3
Serious Adverse Events (SAE) .............................................................................. 55
12.4
Protocol-Related Adverse Events .......................................................................... 56
12.5
Reporting Period .................................................................................................... 57
12.6
Reporting Serious Adverse Events and Subject Deaths ........................................ 57
12.6.1
Timeframe for Reporting ............................................................................. 57
12.6.2
Reporting of Subject Death .......................................................................... 57
12.6.3
Reporting of Overdose ................................................................................. 58
12.6.4
Reporting to the Institutional Review Board/Ethics Committee ................. 58
12.6.5
Information to be Provided by the Investigator ........................................... 59
12.7
Required Follow-up for All Adverse Events and Serious Adverse Events ........... 59
12.8
Pregnancy Reporting .............................................................................................. 60
13
PRECAUTIONS .............................................................................................................. 60
13.1
Precautions Regarding Procreation ........................................................................ 60
13.1.1
Tivozanib ..................................................................................................... 61
13.1.2
Sorafenib ...................................................................................................... 61
13.2
Additional Precautions ........................................................................................... 61
14
DATA EVALUATION AND STATISTICS ................................................................... 61
14.1
General Design....................................................................................................... 61
14.2
Sample Size Justification ....................................................................................... 62
14.3
Statistical Considerations ....................................................................................... 62
14.3.1
Study Populations ........................................................................................ 62
14.3.2
Subject Accountability, Demographics, and Baseline Characteristics ........ 63
14.3.3
Protocol Deviations ...................................................................................... 63
14.3.4
Efficacy ........................................................................................................ 63
14.3.5
Safety Data ................................................................................................... 65
14.3.6
Safety Monitoring Committee ..................................................................... 67
14.3.7
Pharmacokinetic Parameters ........................................................................ 67
14.3.8
Imaging Process ........................................................................................... 67
15
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS .............................................. 67


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15.1
Study Monitoring ................................................................................................... 67
15.2
Audits and Inspections ........................................................................................... 68
16
QUALITY CONTROL AND QUALITY ASSURANCE ............................................... 68
17
ETHICS ............................................................................................................................ 68
17.1
Ethical Conduct of the Study/Conditions of Testing ............................................. 68
17.2
Institutional Review / Ethics Committee ............................................................... 69
17.3
Written Informed Consent ..................................................................................... 69
17.4
Conditions for Modifying or Terminating the Study ............................................. 69
17.4.1
Modification of the Study Protocol ............................................................. 69
17.4.2
Modification of the Informed Consent Document ....................................... 70
17.4.3
Termination of the Study ............................................................................. 70
17.4.4
Deviation From the Protocol ........................................................................ 70
17.5
Documents to be Submitted to the Sponsor ........................................................... 70
18
INVESTIGATOR RESPONSIBILITIES ........................................................................ 71
18.1
Medical Supervision .............................................................................................. 71
18.2
Confidentiality ....................................................................................................... 71
18.3
Use of Information and Publication ....................................................................... 72
18.4
Drug Dispensing Inventory .................................................................................... 72
18.5
Handling and Disposal of Investigational Materials .............................................. 73
18.6
Recording and Processing of Data ......................................................................... 73
18.7
Source Document Requirements ............................................................................ 73
18.8
Laboratory Reports ................................................................................................ 74
18.9
Subject Confidentiality .......................................................................................... 74
19
DATA HANDLING AND RECORDKEEPING ............................................................ 74
19.1
Inspection of Records ............................................................................................ 74
19.2
Retention of Records.............................................................................................. 74
20
REFERENCES ................................................................................................................ 75
21
APPENDICES ................................................................................................................. 77
APPENDIX A
RESPONSE EVALUATION CRITERIA IN SOLID TUMORS 
(RECIST) VERSION 1.1 ..................................................................... 78
APPENDIX B
ECOG PERFORMANCE STATUS EVALUATION ....................... 83
APPENDIX C
CYTOCHROME P450 (CYP3A4) INHIBITORS AND 
INDUCERS ........................................................................................ 84
APPENDIX D
RECOMMENDED ANTI-HYPERTENSIVE MEDICATIONS ...... 85
APPENDIX E
SORAFENIB PRESCRIBING INFORMATION ............................. 86
APPENDIX F
STUDY DRUG INFORMATION ................................................... 105
APPENDIX G
CLINICAL SYMPTOM AND ADVERSE EVENT GRADING 
SCALE ............................................................................................. 108


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APPENDIX H
INTERNATIONAL METASTATIC RENAL CELL 
CARCINOMA DATABASE CONSORTIUM (IMDC) RISK 
MODEL ........................................................................................... 109
LIST OF TABLES 
Table 1:
Study Design and Schedule of Assessments ........................................................ 12
Table 2:
Abbreviations and Specialist Terms ..................................................................... 20
Table 3:
Management of Skin Toxicity Associated with Sorafenib ................................... 50
Table 4:
Dose Modification Guidelines for Drug-Related Adverse Events ....................... 51


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2
LIST OF ABBREVIATIONS AND EXPANDED TERM 
Table 2: 
Abbreviations and Specialist Terms 
Abbreviation or Term 
Expanded Term 
ACE 
angiotensin converting enzyme 
AE 
adverse event 
ALT 
alanine aminotransferase (SGPT) 
ANC 
absolute neutrophil count 
AST 
aspartate aminotransferase (SGOT) 
AUC 
area under the plasma concentration-time curve 
BUN 
blood urea nitrogen 
CBC 
complete blood count 
CFR 
Code of Federal Regulations 
CI  
confidence interval 
CMH 
Cochran-Mantel-Haenszel 
Cmax
maximum (peak) plasma concentration 
CNS 
central nervous system 
CR 
complete response 
CRO 
contract research organization 
Cssav
estimated average serum concentration 
CT 
computerized tomography 
CTCAE 
Common Terminology Criteria for Adverse Events  
(NCI, Version 4.03) 
CV 
curriculum vitae 
CVA 
cerebrovascular accident 
CYP 
cytochrome P450 
DHP 
dihydropyridine 
DLT 
dose limiting toxicity 
DoR 
duration of response 
EC 
Ethics Committee 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EDC 
electronic data capture 
eCRF 
electronic case report form 
EU 
European Union  


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Table 2: 
Abbreviations and Specialist Terms 
Abbreviation or Term 
Expanded Term 
EudraCT 
European Drug Regulatory Affairs Clinical Trials  
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl transferase 
HIV 
human immunodeficiency virus 
HR 
hazard ratio  
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IMDC 
International Metastatic Renal Cell Carcinoma Database Consortium 
IND 
Investigational New Drug 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
IRR 
independent radiological review 
ITT 
intent-to-treat 
IUD 
intrauterine device 
IWRS 
Interactive Web Response System 
LDH 
lactate dehydrogenase 
MCH 
mean cell hemoglobin 
MCV 
mean cell volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
mPFS 
median progression free survival 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
NA 
North America 
NOAEL 
no observed adverse effect level 
NOEL 
no-observable effect level  
ORR 
objective response rate 
OS 
overall survival 
PD 
progressive disease 
PD-1 
programmed cell death -1 protein 
PD1-L 
programmed cell death -1 ligand 


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Table 2: 
Abbreviations and Specialist Terms 
Abbreviation or Term 
Expanded Term 
PDGFR 
platelet derived growth factor receptor 
PE 
physical examination 
PFS 
progression-free survival 
PK 
pharmacokinetic 
PP 
per protocol 
PR 
partial response 
PT 
prothrombin time 
PTT 
partial thromboplastin time 
RCC 
renal cell carcinoma 
RECIST 
Response Evaluation Criteria In Solid Tumors 
SAE 
serious adverse event 
SAF 
safety population 
SAP 
statistical analysis plan 
SD 
stable disease 
SMC 
safety monitoring committee 
SOC 
system organ class 
STD 
standard deviation 
T3 
triiodothyronine  
T4 
thyroxine 
TIA 
transient ischemic attack 
TKI 
tyrosine kinase inhibitor  
TSH 
thyroid stimulating hormone 
tmax
time to peak plasma concentration 
ULN 
upper limit of normal 
US 
United States 
VEGF 
vascular endothelial growth factor 
VEGFR 
vascular endothelial growth factor receptor 
WHO-DD 
World Health Organization Drug Dictionary 


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3
INTRODUCTION   
Tivozanib hydrochloride (tivozanib; previously known as AV-951 and as KRN951) has the 
chemical name (N-{2-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}-N'-(5-methyl-3-
isoxazolyl)urea hydrochloride monohydrate.  Tivozanib is a novel and potent vascular 
endothelial growth factor (VEGF) receptor tyrosine kinase inhibitor (VEGFR TKI) that has 
demonstrated significant anti-tumor effects in pre-clinical experiments [1].  Tivozanib inhibits 
phosphorylation of VEGF receptors (VEGFR) -1, -2 and -3 at picomolar concentrations (IC50
of 0.21, 0.16 and 0.24 nM respectively), and inhibits c-Kit and platelet derived growth factor 
receptor (PDGFR) at 10-times higher concentrations (IC50 of 1.63 and 1.72 nM respectively).   
Based on its biochemical profile, tivozanib appears to be one of the most potent and selective 
VEGF tyrosine kinase inhibitor in clinical development.  Other agents used for treatment of 
renal cell carcinoma (RCC) such as sunitinib and sorafenib inhibit multiple tyrosine kinases in 
addition to the VEGF receptor tyrosine kinase, leading to off-target toxicities such as fatigue, 
hand-foot syndrome, stomatitis, and neutropenia.  The adverse event (AE) profile of tivozanib 
demonstrates that it is a selective VEGF tyrosine kinase inhibitor, with minimal off-target 
toxicities.  
3.1
Background 
Approximately 208,500 new cases of kidney cancer are diagnosed in the world each year, of 
which 40,000 new cases are diagnosed in North America and 63,300 new cases in the 
European Union (EU).  Renal cell carcinoma accounts for 80%-85% of all malignant kidney 
tumors.  Advanced RCC is highly resistant to chemotherapy, and interleukin-2 and 
interferon-α have low levels of anti-tumor activity.  Recently, drugs that block the VEGF 
pathway such as sunitinib, sorafenib, bevacizumab, pazopanib, and axitinib have 
demonstrated significant anti-tumor activity in Phase 3 trials.  As a result, these drugs have 
become the standard of care for the treatment of subjects with advanced RCC. 
The formation of new blood vessels, known as angiogenesis, is required to support growth in 
the embryo and to allow for repair (eg, wound healing and remodeling processes in the adult) 
[2].  Vascular endothelial growth factor plays a critical role during normal embryonic 
angiogenesis and also in the pathological angiogenesis that occurs in a number of diseases, 
including cancer [3,4].  Tumors use this vasculature to obtain oxygen and nutrients, both of 
which are required to sustain tumor growth.  In addition, the new intra-tumoral blood vessels 
provide a way for tumor cells to enter the circulation and to metastasize to distant organs [5].  
The various forms of VEGF bind to 3 tyrosine kinase receptors:  the vascular endothelial 
growth factor receptors, VEGFR-1, VEGFR-2, and VEGFR-3 retrospectively.  This binding 
results in phosphorylation of the receptors catalyzed by the protein kinase, and the promotion 
of a signal transduction cascade.  Deregulation of VEGF expression contributes to the 
progression and spread of solid tumors by promoting tumor angiogenesis [6].  Tivozanib 
inhibits VEGFR-associated tyrosine kinase activity and, as a result, may offer a potential 
therapy for subjects with cancer by controlling tumor growth. 
3.2
Pharmacology  
In cellular assays, tivozanib has been shown to inhibit markedly VEGF-induced 
phosphorylation of intracellular VEGFR-1, VEGFR-2, and VEGFR-3 (IC50 of 0.21 nmol/L, 


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0.16 nmol/L, and 0.24 nmol/L, respectively).  Tivozanib, administered orally at 5 and 
20 mg/kg once daily for 2 weeks, demonstrated a broad spectrum of anti-tumor effects against 
lung, colon, and prostate carcinoma xenografts in nude mice. 
Even at lower doses, tivozanib demonstrated a broad spectrum of anti-tumor effects.  
Tivozanib given orally at a dose of 0.2 mg/kg once daily for 2 weeks showed statistically 
significant inhibitory effects (P<0.05) on the growth of various tumor xenografts [1].  
Tivozanib at a dose of 1.0 mg/kg exerted tumor regression on human breast adenocarcinoma 
MDA-MB231, human colon adenocarcinoma LoVo, human renal carcinoma Caki-1, and 
human prostate carcinoma DU145 xenografts. 
Tivozanib has been shown to inhibit both angiogenesis and vascular permeability in tumor 
tissues.  Immunostaining of endothelial cells of tumor tissues in a human lung carcinoma 
A549 xenograft demonstrated a dose-dependent decrease in microvessel density in tumor 
tissues after oral administration of tivozanib (0.04, 0.2, and 1.0 mg/kg) once daily over 
1 week.  When Evans blue was injected intravenously in a similar animal model to examine 
the transfer of dye into the tumor tissues, tivozanib reduced the quantity of dye transferred to 
the tumor tissues in a dose-dependent manner, suggesting a reduction in vascular 
permeability, which could limit the availability of nutrients to the tumor thereby inhibiting 
tumor growth. 
Based on the above results, tivozanib is expected to exhibit a broad anti-tumor spectrum of 
activities against various tumors by inhibiting angiogenesis and vascular permeability.  
3.3
Safety Pharmacology 
Based on the Irwin Test, there were no significant behavioral or physiological changes 
observed in rats during the 24-hour post-dose period after receiving a single oral dose of 0.3, 
3, 30, or 400 mg/kg tivozanib compared to vehicle-treated animals.  In a telemetry study in 
monkeys, doses of 0.015 or 0.3 mg/kg tivozanib were shown to have no significant effects on 
arterial blood pressure; however, increasing this dose to 3.0 mg/kg resulted in transient 
increases in systolic, diastolic, and mean arterial blood pressure by up to 14–19 mmHg.  
Tivozanib was not shown to have a marked effect on any other cardiovascular or respiratory 
parameters. 
3.4
Toxicology 
Repeat-dosing studies with tivozanib have been conducted in rats and monkeys.  In a 28-day 
rat study of 0.3 and 0.1 mg/kg/day, the 0.1 mg/kg/day dose was considered to be the no 
observed adverse effect level (NOAEL) in the rat as based on clinical signs, laboratory 
findings, and histopathological changes.  In a 28-day repeat-dose study in monkeys, 
0.230-0.3 mg/kg/day was considered to be the NOAEL based on clinical signs, laboratory 
findings, and histopathological changes. 
In a 13-week, repeated-dose study in the rat at dosages of 0.01, 0.03, 0.1 and 0.3 mg/kg/day, 
exposure to tivozanib at 0.3 mg/kg/day resulted in 3 male and 2 female unscheduled deaths 
considered to be drug related.  The cause of death was microscopically determined to be 
adrenal necrosis/degeneration in these rats.  Administration of 0.1 mg/kg/day tivozanib was 
associated with abnormal clinical signs, such as hunched appearance, thin appearance, rough 
hair coat, yellow hair coat, white teeth, and malocclusion.  Marked body weight loss 


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accompanied by significant decreases in food consumption occurred in 0.3 mg/kg/day.  
Hematological investigations revealed lower relative and absolute reticulocyte counts in most 
0.3 mg/kg/day rats, which may represent a transient effect of tivozanib.  The mean cell 
volume (MCV) and mean cell hemoglobin (MCH) were also elevated, and there were higher 
white blood cell, lymphocyte, neutrophil, and monocyte counts in the 0.3 mg/kg/day rats.  In 
blood chemistry investigation, treatment-associated changes were noted in alanine 
aminotransferase (ALT), bile acids, gamma-glutamyl transferase (GGT), iron metabolism 
parameters, and serum iron.  Histopathological examination of tissues showed abnormalities 
in the adrenal grand, kidney, femur, liver and bile ducts, and incisors.  Pronounced changes 
considered secondary to bile duct inflammation were seen in the pancreas and duodenum.  
Most findings resolved or showed signs of ongoing reversal after the withdrawal of treatment.  
However, kidney lesions were not resolved at either recovery or sacrifice.  Based on these 
findings, mechanistic studies were conducted to better understand the adverse effect on the 
kidney.  In conclusion, based on all study findings, the no-observable effect level (NOEL) was 
less than 0.01 mg/kg/day.  Based on body weight effects in females, the NOAEL was 
0.01 mg/kg/day.  Some tivozanib-related effects persisted through the end of the recovery 
periods, and many were seen to a much lesser degree.   
In the 13-week repeat dose monkey study at doses of 0.01, 0.03, 0.1 and 0.3 mg/kg/day, no 
mortality occurred.  Clinical observations of dehydration; hunched posture; thin appearance; 
hypoactivity; discolored, few/no and/or non-formed feces; low/no food consumption and/or 
body weight loss were seen at 1.0 mg/kg/day.  Low/no food consumption and/or body weight 
loss were observed at 0.3 mg/kg/day, and an increased frequency of low/no food consumption 
was also noted at 0.1 mg/kg/day.  Findings were generally unremarkable during recovery.  No 
tivozanib effects were observed in ophthalmic and electrocardiogram (ECG) examination.  
There were no toxicologically significant changes in hematology, serum and urine chemistry, 
and urinalysis data during treatment or recovery.  Tivozanib-related histopathological 
alterations at 1.0 mg/kg/day consisted of gastroenteropathy; decreased pancreatic zymogen 
granules; atrophy of the primary spongiosa and hypertrophy of the physis in the distal femur 
and tibia; hypertrophy of femoral articular cartilage; degeneration of the adrenal cortex; 
mononuclear infiltrates, thrombi, hemorrhage, and pigment deposition in the cerebral 
ventricular choroid; and lymphoid depletion of lymphoid organs (spleen, thymus, lymph 
nodes).  Tivozanib-related histopathological alterations observed primarily at 0.3 mg/kg/day 
and in a few 0.1 mg/kg/day monkeys consisted of mononuclear cell infiltrates in the choroid 
plexus of the brain; adrenal cortical degeneration (increased cytoplasmic eosinophilia and/or 
decreased vacuolization); decreased pancreatic zymogen granules and decreased cytoplasmic 
granules in parotid salivary glands; lymphoid depletion in thymus, spleen and mandibular 
lymph node; and atrophy of the primary spongiosa of the metaphysis (femur and/or 
tibia/fibula).  The 13-week NOAEL in monkeys was considered 0.03 mg/kg/day.  Findings 
after recovery indicated reversal or abatement of tivozanib-related changes.   
Tivozanib did not produce genotoxic effects in any of the systems tested.   
FOR ADDITIONAL INFORMATION, PLEASE REFER  
TO THE TIVOZANIB (AV-951) INVESTIGATOR’S BROCHURE 


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3.5
Pharmacokinetics 
Pharmacokinetic (PK), toxicokinetic, and metabolic disposition studies were conducted with 
tivozanib in rats and monkeys, and PK data are available from a Phase 1 clinical trial in 
humans.  In rats and monkeys, peak serum concentrations of tivozanib were attained 
approximately 3–6 hr after oral administration, and the t½ values averaged 7-12 hr.  
In the nude rat, the estimated average serum tivozanib concentration (Cssav) at steady state 
after oral doses of 0.2 mg/kg/day (the lowest dose with minimum efficacy in this animal 
model) was 70 ng/mL.   
In the rat and monkey, after both single and multiple oral doses of tivozanib, maximum (peak) 
plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) were 
approximately dose proportional.   
3.6
Previous Human Experience 
3.6.1
Pharmacokinetics in Subjects with Solid Tumors 
Final PK data are available from Study KRN951/03-B01, completed in subjects with solid 
tumors.  PK data were collected from a total of 41 subjects and included all who had taken at 
least one dose of tivozanib.  Three doses of tivozanib were studied (1.0, 1.5, and 2.0 mg) in a 
regimen of 4 weeks of daily dosing followed by a 14-day rest period.  Each 6-week regimen 
was considered one cycle.   
After single and multiple doses of tivozanib, the overall rate of absorption was slow.  Median 
time to peak serum concentration (tmax) of tivozanib ranged from 2 to 24 hours with 
substantial individual variability.  The time to peak serum concentration was variable due to 
the occurrence of secondary peaks in the concentration versus time profiles indicating the 
possibility of enterohepatic recirculation of tivozanib.   
Although the inter-subject variability was high, mean Cmax and AUC values after single and 
multiple doses were approximately dose proportional.  An evaluation of the available data 
predicted that tivozanib has a mean half-life across dose groups of approximately 4.7 days 
(112 hours) and ranging from 1.3 to 9.7 days (31 – 233 hours) (data not included in tables).  
Due to the unexpectedly long half-life of tivozanib in humans, sufficient timepoints to 
characterize the terminal phase were not available from all subjects.   
AUCs on Day 28 were higher than those on Day 1 indicating drug accumulation.  In the 
majority of subjects, pre-dose samples collected prior to the first dose of Cycle 2, (ie, 14 days 
after administration of the previous dose on Day 28 of Cycle 1) still had detectable 
concentrations of tivozanib in serum indicating ongoing drug exposure during the 14-day 
dosing break at the end of Cycle 1.   
3.6.2
Clinical Activity 
TIVO-1 (AV-951-09-301) was an open-label, randomized, controlled, multi-national, 
multi-centre, parallel-arm trial comparing tivozanib (1.5 mg/day for 3 weeks on, 1 week off, 
continuously) to sorafenib (400 mg bid continuously) in patients with advanced RCC.  
Patients had undergone prior nephrectomy, and approximately 70% had received no prior 
systemic therapy in the metastatic setting.  The remaining patients had received one prior line 


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of therapy in the metastatic setting, the vast majority of which was cytokine treatment.  Prior 
therapy with an anti-angiogenesis agent was not allowed.  
The design of the study was such that patients with radiological evidence of progressive 
disease (PD) per investigator/local radiology assessment continued treatment until PD was 
verified by an independent radiologist.  Patients randomized to the sorafenib treatment arm 
who had verified PD (by an independent radiologist) were discontinued from study drug 
treatment and given the option to receive tivozanib under a separate extension protocol 
(AV-951-09-902).  Patients who were discontinued from sorafenib treatment owing to the 
development of AEs or non-radiographic confirmed progression were not eligible to receive 
tivozanib.  Patients randomised to the tivozanib treatment arm who had radiological evidence 
of PD per investigator/local radiology assessment continued treatment until PD was verified 
by an independent radiologist, after which they were discontinued from study drug treatment 
but were not provided sorafenib per protocol.  Instead, these patients could only receive 
second line therapy consistent with the practices in the patient’s home country. 
Superiority was shown for the primary endpoint, progression-free survival (PFS), based upon 
blinded independent radiological assessment (per Response Evaluation Criteria in Solid 
Tumors [RECIST] Version 1.0 definition).  The blinded independent radiological assessment 
showed the Median progression free survival (mPFS) in the tivozanib arm to be 11.9 months 
(95% confidence interval (CI) [9.3, 14.7]), compared with 9.1 months (95% CI [7.3, 9.5]) in 
the sorafenib arm.  This is a statistically significant improvement in mPFS, with a p-value of 
0.042, and a hazard ratio (HR) of 0.797 (95% CI [0.639, 0.993]).  
Additional key efficacy endpoints, including independent assessment of objective response 
rate (ORR) and duration of stable disease were statistically significantly improved for 
tivozanib, compared with sorafenib.  Forest plots assessing the efficacy of tivozanib vs. 
sorafenib in multiple subgroups showed consistent benefit of tivozanib over sorafenib.  
There was a slight difference in overall survival (OS), favoring the sorafenib randomized arm 
over the tivozanib randomized arm (29.3 months vs 28.8 months; p-value 0.105; HR 1.245 
[95% CI: 0.954, 1.624]). 
Evidence of Second Line Efficacy 
The updated analysis of the second line efficacy data (cut-off date of 24th April 2014) from 
study AV-951-09-902 has revealed that the mPFS for patients in the sorafenib arm who 
received tivozanib subsequent to sorafenib treatment is 11.0 months (95% CI [7.4, 12.9]).  
The overall median survival for this group was 21 months from the start of tivozanib.  This 
strong second line efficacy of tivozanib in those patients who crossed over from sorafenib to 
tivozanib likely drives the discordance between the PFS and OS endpoints.  
Impact of the Unbalanced Use of Second Line Therapy  
The one-way crossover design of the pivotal trial allowed patients who experienced 
radiographic disease progression on sorafenib to crossover to the experimental arm, but not 
vice versa.  This created an imbalance in second-line treatment between arms, particularly 
outside the EU and United States (US) where second-line therapies were not generally 
available.  Owing to this imbalance, significantly more patients from the sorafenib arm who 
experienced disease progression were subsequently treated with next line targeted therapy (the 


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majority of which was tivozanib) compared with patients randomized to the experimental arm 
(tivozanib followed by off-protocol next line targeted therapy).  At the time of the prior NDA 
submission (September 2012) 13% of patients randomized to tivozanib had received targeted 
next line treatment with TKI vs 63% of patients randomized to sorafenib who received second 
line tivozanib.  An updated analysis of the second line data indicates that as of December 
2014 even more patients in the sorafenib arm (approx. 70%) have received second line 
tivozanib following disease progression; whereas, only 36% of the patients randomized to the 
tivozanib arm who subsequently experienced disease progression have received targeted next 
line therapy. 
To further understand the effect of crossover on OS in Study AV-951-09-301 an analysis was 
performed on the 186 patients enrolled in the study in the EU and North America (NA) (NA; 
US and Canada). The participating countries were Bulgaria, Canada, Czech Republic, France, 
Hungary, Italy, Poland, Romania, UK, and the US.  In these territories the standard of care is 
more likely to include second line therapies and therefore mitigate the effect of the one-way 
crossover.  This analysis revealed that for the NA and EU region while the significant benefit 
for PFS remains for the tivozanib arm, the non-significant trend in OS favors the tivozanib 
arm as well.  The OS for the tivozanib arm was 35.9 months versus 31.0 months for the 
sorafenib arm (p-value 0.576; HR 0.892 [95% CI: 0.599, 1.329]).   
Consequently, the OS data do not provide an accurate measure of relative survival against the 
comparator in this study.  Nevertheless, with this caveat in mind, OS values for the sorafenib 
arm and the tivozanib arm were amongst the longest seen in pivotal RCC trials.  
To conclude, the evidence provided above indicates that the imbalance in crossover between 
the two treatment arms in the pivotal trial and the strong second line efficacy of tivozanib 
observed in the patients who crossed over from sorafenib to tivozanib confounded the OS data 
and likely explains the discordance between the PFS and OS endpoints seen in the overall 
analysis, and as such makes the OS results difficult to interpret.  
Consolidated Safety Data 
The AE profile for tivozanib in the TIVO-1 trial (Study AV-951-09-301) is consistent with 
the prior Phase 2 experience (AV-951-07-201).  Comparable rates of serious adverse events 
(SAEs) and AEs with fatal outcomes occurred in each arm. 
AEs that were more common in the tivozanib arm than in the sorafenib arm included 
hypertension (44.0% vs 34.2%) and dysphonia (20.5% vs 4.7%).  AEs that were more 
common in the sorafenib arm than in the tivozanib arm included hand-foot syndrome (54.1% 
vs 13.1%), skin rashes (17.2% vs 4.7%); and diarrhoea (31.5% vs 21.6%).  Other common 
AEs were similar in both arms, including fatigue, asthenia, and weight decrease (all ~15-
20%).  Fewer grade 3 or higher AEs occurred in the tivozanib arm than in the sorafenib arm 
(56.8% vs 68.5%).  More grade 3 or higher hypertension events were observed in the 
tivozanib arm (24.7% vs 17.1%) and more grade 3 or greater hand-foot syndrome events were 
observed in the sorafenib arm (16.7% vs 1.9%).  Ischemia cerebrovascular AEs occurred in 
2.7% of patients on the tivozanib arm and in 1.6% of patients on the sorafenib arm. 
Cardiovascular AEs were similar in each arm.  Grade 3 or higher liver enzyme perturbations 
were less frequent with tivozanib compared to sorafenib and proteinuria was similar between 
the two arms. 


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Fewer patients in the tivozanib group had dose interruptions (54, [20.8%] patients) compared 
with those in the sorafenib group (99, [38.5%] patients).  Furthermore, fewer patients who 
received tivozanib had dose reductions overall (29, [11.2%] patients) compared to sorafenib 
patients (96, [37.4%] patients).  More subjects in the tivozanib group had dose interruptions 
for hypertension (5.4% vs 3.5%), and more subjects in the sorafenib group had dose 
interruptions for hand-foot syndrome, diarrhoea, and asthenia (16.7% vs 1.9% and 3.5% vs 
1.9% and 1.9% vs 0.8%).  More subjects in the sorafenib group had dose reductions for 
hand-foot syndrome, diarrhoea, hypertension, and lipase increased compared with the 
tivozanib group (17.9% vs 1.9%; 4.3% vs 1.5%; 4.3% vs 1.5%, and 2.3% vs 0.4% 
respectively).  Less than 2% of subjects had a dose reduction for asthenia or fatigue in either 
group.  These dose interruption and reduction data suggest an improved patient tolerability for 
tivozanib versus sorafenib. 
3.7
Study Rationale  
3.7.1
Rationale for the Tivozanib Dose 
In Study KRN951/03-B01, 3 of 8 subjects in the 2 mg tivozanib group experienced a dose 
limiting toxicity (DLT), indicating that the maximum tolerated dose (MTD) had been 
exceeded.  Based on the results of this study, the MTD was determined to be 1.5 mg/day, and 
the safety of this dose has been confirmed in multiple subsequent studies. 
3.7.2
Rationale for the Tivozanib Dosing Regimen 
The initial Phase 1 clinical study (KRN951/03-B01) adopted a dosing regimen with 28-day 
continuous administration of tivozanib followed by 14-day rest period (during which time no 
study drug is administered).  This study demonstrated that the MTD of tivozanib is 
1.5 mg/day, and that toxicities are rapidly reversible upon stopping treatment.  The dosing 
regimen was altered for Study AV-951-07-201 to 21-day (3 weeks) continuous administration 
of tivozanib followed by 7-day (1 week) rest period during which no study drug is 
administered.  The rationale for changing the dosing regimen was to minimize the rest period 
during treatment but yet allow subjects to recover from any treatment-related toxicity during 
the 7-day break.  Clinical data with sunitinib have demonstrated that subjects experience 
recurrence of disease-related symptoms during a 14-day break in treatment [7].  Therefore, the 
break in tivozanib dosing was reduced from 14-days (Study KRN951/03-B01) to 7 days 
(Study AV-951-07-201) in an effort to maximize clinical benefit to subjects.  The 1.5 mg/day 
dose given continuously for 21-days followed by a 7-day break has been well tolerated in 
272 subjects enrolled in Study AV-951-07-201, and to date only 23 (8.5%) subjects have 
required a dose reduction and 8 (2.9%) have required a dose interruption.  Therefore, this 
dosing regimen will be used in this Phase 3 study.   
3.7.3
Rationale for the Study Design 
This is a randomized, controlled, open-label, multicenter study comparing tivozanib to 
sorafenib in subjects with refractory advanced RCC. Tivozanib has demonstrated significant 
activity in the second line therapy as described above.  Sorafenib was chosen as a comparator 
for this Phase 3 trial because sorafenib is no longer the most commonly used first line VEGFR 
inhibitor and is used in advanced RCC. Subjects will be randomized (1:1) to treatment with 
tivozanib or sorafenib.  As differences in such factors as co-medications, prior treatments, and 
palliative care may affect enrollment rates across the participating centers, the randomization 


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of subjects will be stratified by the International Metastatic Renal Cell Carcinoma Database 
Consortium (IMDC) risk category (favorable; intermediate; poor) and prior therapy (two prior 
VEGFR TKIs; a prior checkpoint inhibitor [programmed cell death -1 protein (PD-1) or PD-1 
ligand (PD1-L) inhibitor] plus a prior VEGFR TKI; a prior VEGFR TKI plus any other 
systemic agent).  To protect the integrity of the primary endpoint, progression-free survival 
will be assessed by an outside group of independent radiology reviewers.  
3.7.4
Use in Pregnancy 
Tivozanib should not be administered to pregnant women, as it is known that angiogenesis 
plays an important role in reproductions and embryonic development.  It is required that 
women of childbearing potential undergo a pregnancy test before treatment and must use 
adequate contraceptive measures while on study and for at least 90 days after the last dose of 
study drug.  Sexually active male subjects must use adequate contraceptive measures, while 
on study and for at least 90 days after the last dose of study drug.  Risk to male sperm is 
unknown.  Effective contraceptive measures include (a) intrauterine device (IUD) plus one 
barrier method; or (b) 2 barrier methods.  Effective barrier measures are male or female 
condoms, diaphragms, and spermicides (creams or gels that contain a chemical to kill sperm).  
Oral, implantable, or injectable contraceptives may be affected by cytochrome P450 
interactions, and are not considered effective for this study. 
FOR ADDITIONAL INFORMATION, PLEASE REFER  
TO THE TIVOZANIB (AV-951) INVESTIGATOR’S BROCHURE 
3.7.5
Potential Risks/Benefits of Therapy With Sorafenib (Nexavar) 
Sorafenib is currently approved for the treatment of advanced RCC and unresectable 
hepatocellular carcinoma, and locally recurrent or metastatic, progressive differentiated 
thyroid cancer.  Sorafenib was approved in the US on 20 December 2005 as the first VEGF 
receptor inhibitor for the treatment of advanced RCC.  Sorafenib received marketing 
authorization by the European Commission on 19 July 2006 for the treatment of subjects with 
advanced RCC who have failed prior interferon-alpha or interleukin-2 based therapy or are 
considered unsuitable for such therapy.  These approvals were based on the demonstration of 
an improvement in median PFS (sorafenib 167 days [5.5 months]; placebo 84 days 
[2.8 months]) in a large multinational, randomized, double-blind, placebo-controlled, Phase 3 
study of sorafenib vs. placebo, along with a supporting Phase 2, randomized, discontinuation 
trial in subjects with advanced RCC.  Adverse events most frequently observed (≥ 20%) with 
sorafenib are fatigue, weight loss, rash/desquamation, hand-foot skin reaction, alopecia, 
diarrhea, anorexia, nausea, and abdominal pain.  Overall, the most frequently observed 
laboratory abnormalities include neutropenia, thrombocytopenia, anemia, lymphopenia, 
hypophosphatemia, and elevated lipase. 
FOR ADDITIONAL INFORMATION, PLEASE REFER TO APPENDIX E 
(SORAFENIB PRESCRIBING INFORMATION) FOR A DESCRIPTION OF 
TOXICITIES OBSERVED IN HUMANS TO DATE. 


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4
STUDY OBJECTIVES AND PURPOSE 
4.1
Primary Objective 
The primary objective of this study is as follows: 
•
To compare the PFS of subjects with refractory advanced RCC randomized to 
treatment with tivozanib or sorafenib as assessed by blinded independent 
radiological review (IRR) of computerized tomography (CT) or magnetic 
resonance imaging (MRI). 
4.2
Secondary Objectives 
The secondary objectives of this study are as follows: 
•
To compare the OS of subjects randomized to treatment with tivozanib or 
sorafenib 
•
To compare ORR and duration of response (DoR) of subjects randomized to 
treatment with tivozanib or sorafenib  
•
To compare the safety and tolerability of tivozanib and sorafenib. 
4.3
Tertiary Objectives 
The tertiary objectives of this study are as follows: 
•
To explore any relationship between: 
−
tivozanib and sorafenib drug levels and activity 
−
tivozanib and sorafenib drug levels and AEs 
5
INVESTIGATIONAL PLAN 
5.1
Overall Study Design and Plan: Description 
This is an open-label, randomized, controlled, multi-national, multi-center, parallel-arm study 
comparing tivozanib to sorafenib in subjects with refractory advanced RCC.  The study is 
designed to compare the PFS, OS, ORR, DoR, safety and tolerability, of tivozanib and 
sorafenib.   
Subjects will be randomized (1:1) to treatment with tivozanib or sorafenib and stratified by 
IMDC risk category (favorable; intermediate; poor) and prior therapy (two prior VEGFR 
TKIs; a prior checkpoint inhibitor [PD-1 or PD1 L inhibitor] plus a prior VEGFR TKI; a prior 
VEGFR TKI plus any other systemic agent).  Once the strata have been identified, treatment 
will be randomly assigned to a subject within the strata using a complete permuted block 
design, in an unblinded fashion (open–label). In the event a subject had both 2 TKIs and a 
checkpoint inhibitor, the subject will be stratified according to the most recent line of therapy. 
Subjects must begin treatment with study drug within 14 days after randomization. 


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5.2
Approximate Duration of Study 
It is anticipated that enrollment to this study will be completed in approximately 15 months.  
A follow-up period of 6 months is expected.  Overall duration of subject participation is 
approximately 24 months.   
5.3
Approximate Number of Subjects 
Approximately 322 subjects with refractory advanced RCC are planned to participate in this 
study at approximately 160-190 sites.   
Anticipated date of enrollment of first subject:  June 2016 
Anticipated date of enrollment of last subject:  August 2017 
Established data cut-off date (targeted number of 242 PFS events): 04 October 2018 
5.4
Subject Enrollment 
Subject enrollment will take place before the start of study drug administration.  Written 
informed consent must be obtained and all eligibility criteria must be met at the time of 
enrollment.  An Interactive Web Response System (IWRS) will be used for enrollment, 
randomization and drug management (packaging of clinical supplies, shipping to study sites, 
and dispensing to subjects). 
5.4.1
Subject Enrollment Assignment 
Each subject will be assigned a 6-digit identification code.  This code will consist of:   
•
3-digit site code (Example:  101):  assigned by the Sponsor at the time of study 
initiation. 
•
3-digit subject code (Example:  001):  assigned by the site via IWRS at the time 
written informed consent is obtained and screening has begun.  Each site will 
begin with Subject 001. 
In the case of re-screening, the same screening number will be used and there is no limit on 
the number of times re-screening is allowed. There is no window limitation in between the 
different screening attempts for the same subject. 
5.4.2
Treatment Randomization 
Once informed consent has been obtained and all eligibility criteria have been met, subjects 
will be randomized 1:1 to tivozanib or sorafenib using an IWRS.  Subjects must begin 
treatment with study drug within 14 days after randomization.  Specific instructions for use of 
the enrollment/randomization system will be provided in a separate manual.   
6
DIAGNOSIS AND MAIN CRITERIA 
6.1
Subject Inclusion Criteria 
Subjects may be male or female, and must meet all of the following inclusion criteria to be 
eligible for participation in the study. 
1. ≥ 18-years of age. 


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2. Subjects with metastatic RCC who have failed 2 or 3 prior systemic regimens, one of 
which includes a VEGFR TKI other than sorafenib or tivozanib. 
a. Postoperative or adjuvant systemic therapy will not be counted as a prior therapy 
unless recurrence is detected within 6 months of completion of treatment, in which 
case it will be counted as a prior therapy for metastatic disease. 
b. Subjects must be off all systemic anti-cancer therapy or radiotherapy for at least 
2 weeks prior to Cycle 1 Day 1. 
3. Subjects must have recovered from the AEs of prior therapy or returned to baseline. 
Controlled AEs such as hypothyroidism or hypertension are permitted. 
4. Histologically or cytologically confirmed RCC with a clear cell component (subjects with 
pure papillary cell tumor or other non-clear cell histologies, including collecting duct, 
medullary, chromophobe, and unclassified RCC are excluded). 
5. Measurable disease per the RECIST criteria (Version 1.1, see Appendix A).   
6. ECOG performance status of 0 or 1. 
7. Life expectancy ≥ 3 months.  
8. If female and of childbearing potential, documentation of negative pregnancy test prior to 
enrollment.   
9. Ability to give written informed consent and comply with protocol requirements. 
10. Sexually active pre-menopausal female subjects (and female partners of male subjects) 
must use adequate contraceptive measures, while on study and for at least 90 days after 
the last dose of study drug.  Sexually active male subjects must use adequate contraceptive 
measures, while on study and for at least 90 days after the last dose of study drug.  All 
fertile male and female subjects and their partners must agree to use a highly effective 
method of contraception.  Effective birth control includes (a) IUD plus one barrier 
method; or (b) 2 barrier methods.  Effective barrier methods are male or female condoms, 
diaphragms, and spermicides (creams or gels that contain a chemical to kill sperm).  
(Note:  oral, implantable, or injectable contraceptives may be affected by cytochrome 
P450 interactions, and are not considered effective for female subjects in this study.) 
6.2
Subject Exclusion Criteria 
Subjects meeting any of the following criteria are ineligible for participation in the study. 
1. Prior treatment with sorafenib or tivozanib. 
2. More than 3 prior regimens for metastatic RCC. 
3. Known central nervous system (CNS) metastases other than stable, treated brain 
metastases. Subjects with previously treated brain metastasis will be allowed if the brain 
metastasis has been stable by neuroimaging without steroid treatment for at least 3 months 
following prior treatment (radiotherapy or surgery). 
4. Any of the following hematologic abnormalities:  
•
Hemoglobin < 9.0 g/dL (packed red blood cell transfusion is permitted) 


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•
Absolute neutrophil count (ANC) < 1500 per mm3
•
Platelet count < 100,000 per mm3. 
5. Any of the following serum chemistry abnormalities: 
•
Total bilirubin > 1.5 × upper limit of normal (ULN) (or > 2.5 × ULN for subjects 
with Gilbert’s syndrome) 
•
Aspartate aminotransferase (AST) or ALT > 2.5 × ULN (or > 5 × ULN for 
subjects with liver metastasis) 
•
Alkaline phosphatase > 2.5 × ULN (or > 5 × ULN for subjects with liver or bone 
metastasis) 
•
Creatinine > 1.5 × ULN unless the creatinine clearance is > 40 mL/min. Creatinine 
clearance can be calculated by standard equations (eg, Cockroft-Gault) or 
measured. 
6. Significant cardiovascular disease, including: 
•
Active clinically symptomatic left ventricular failure. 
•
Uncontrolled hypertension:  Systolic blood pressure > 150 mmHg or diastolic 
blood pressure > 100 mmHg on 2 or more antihypertensive medications, 
documented on 2 consecutive measurements taken at least 2 hours apart. 
•
Myocardial infarction, severe angina, or unstable angina within 6 months prior to 
administration of first dose of study drug. 
•
History of serious ventricular arrhythmia (ie, ventricular tachycardia or ventricular 
fibrillation). 
•
Cardiac arrhythmias requiring anti-arrhythmic medications (except for atrial 
fibrillation that is well controlled with anti-arrhythmic medication). 
7. Non-healing wound, bone fracture, or skin ulcer. 
8. Active peptic ulcer disease, inflammatory bowel disease, ulcerative colitis, or other 
gastrointestinal condition with increased risk of perforation; history of abdominal fistula, 
gastrointestinal perforation, or intra-abdominal abscess within 4 weeks prior to 
administration of first dose of study drug. 
9. Serious/active infection or infection requiring parenteral antibiotics. 
10. Inadequate recovery from any prior surgical procedure or major surgical procedure within 
4 weeks prior to administration of first dose of study drug. 
11. Significant thromboembolic or vascular disorders within 6 months prior to administration 
of first dose of study drug, including but not limited to: 
•
Symptomatic pulmonary embolism 
•
Cerebrovascular accident (CVA) or transient ischemic attack (TIA) 
•
Peripheral arterial ischemia > Grade 2 


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•
Coronary or peripheral artery bypass graft.  
12. Significant bleeding disorders within 6 months prior to administration of first dose of 
study drug, including but not limited to: 
•
Hematemesis, hematochezia, melena or other gastrointestinal bleeding ≥ Grade 2 
•
Hemoptysis or other pulmonary bleeding ≥ Grade 2 
•
Hematuria or other genitourinary bleeding ≥ Grade 2.  
13. Currently active second primary malignancy, including hematologic malignancies 
(leukemia, lymphoma, multiple myeloma, etc), other than non-melanoma skin cancers, 
non muscle-invasive urothelial cancer, non-metastatic prostate cancer, in situ cervical 
cancer and ductal or lobular carcinoma in situ of the breast.  Subjects are not considered to 
have a currently active malignancy if they have completed anti-cancer therapy and have 
been disease free for >2 years.  
14. Pregnant or lactating females.  
15. History of genetic or acquired immune suppression disease such as human 
immunodeficiency virus (HIV), subjects on immune suppressive therapy for organ 
transplant. 
16. Life-threatening illness or organ system dysfunction compromising safety evaluation.  
17. Requirement for hemodialysis or peritoneal dialysis.  
18. Inability to swallow pills, malabsorption syndrome or gastrointestinal disease that severely 
affects the absorption of tivozanib or sorafenib, major resection of the stomach or small 
bowel, or gastric bypass procedure. 
19. Psychiatric disorder or altered mental status precluding informed consent or necessary 
testing.  
20. Participation in another interventional protocol. 
6.3
Drugs and Other Treatments to be Excluded  
The following medications/treatments are prohibited during the study: 
1. Chemotherapy, biological therapy (including cytokines, signal transduction inhibitors, 
monoclonal antibodies), immunotherapy or any other therapy for RCC. 
2. Systemic hormonal therapy, with the exception of: 
•
Hormonal therapy for appetite stimulation or contraception 
•
Nasal, ophthalmic, inhaled and topical steroid preparations 
•
Androgen suppression therapy for non-metastatic prostate carcinoma 
•
Hormone replacement therapy for conditions such as adrenal insufficiency, 
hypothyroidism, etc. 
•
Low-dose maintenance steroid therapy (equivalent of prednisone ≤ 10 mg/day) for 
other conditions. 


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3. Treatment with radiotherapy. 
4. Herbal preparations/supplements (including daily multivitamin/mineral supplement 
containing herbal components) or topical ointments containing herbal components. 
5. Treatment with strong cytochrome P450 (CYP3A4) inducers or inhibitors (see 
Appendix C). 
6. Treatment with full dose oral anticoagulants such as warfarin, acenocoumarol, 
fenprocoumon, or similar agents unless they have been on a stable dose for more than 
2 weeks prior to enrollment.  Full dose anticoagulation with low molecular weight heparin 
or unfractionated heparin administered subcutaneously is allowed. 
7
TREATMENT OF SUBJECTS 
Study drug is to be administered only to subjects who have provided informed consent and 
meet all of the criteria outlined in Sections 6.1, Subject Inclusion Criteria, and 6.2, Subject 
Exclusion Criteria. 
7.1
Procedures/Parameters to be Measured 
See the Study Flowchart (Table 1, beginning on page 12) for the timing of the procedures to 
be performed at each visit. 
All subjects will be assessed by scheduled clinical, laboratory, and other diagnostic 
assessments throughout the study.  Subjects will be treated on an outpatient basis, unless 
hospitalization is required for other reasons. 
Subjects must voluntarily sign and date the study-specific Institutional Review Board 
(IRB)/Ethics Committee (EC)-approved informed consent before any study-related 
procedures (with the exception of disease assessment for screening if it was completed as part 
of standard of care) are performed. 
All screening assessments are to be performed within 21 days prior to first study drug dose, 
unless otherwise specified. 
The day of first study drug administration will be considered Day 1 of the study.   
Clinic visits will take place according to the schedule of assessments.  The visit window of 
± 2 working days does not apply to study drug administration.  Visit assessments will be 
performed prior to administration of the study drug for that day.   
If significant changes from baseline are noted during the course of the study, additional 
unscheduled clinic visits may be undertaken by the investigator, or requested by the sponsor, 
in order to determine both the relevance of the finding(s) and the duration of the event(s). 
All end-of-treatment assessments are to be performed within 7 days following the last study 
drug dose unless delayed due to the occurrence of an adverse event.  Note:  subjects starting 
any new anti-cancer therapy must complete the End-of-Treatment Visit prior to starting the 
new anti-cancer therapy.   
A follow-up visit will be performed 30 days (± 7 days) following the last dose of study drug. 
After the 30-Day Follow-up visit, subjects will be contacted once every 3 months by the site 
to collect long-term survival data.


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Informed Consent 
All subjects must take part in the informed consent process.  Adequate time must be allowed 
for the subject to ask questions and make a voluntary decision.  No protocol specific 
procedures, including screening procedures are to be performed until the subject has signed 
and dated an IRB/EC approved informed consent form (ICF).  The signing of the ICF can 
occur outside of the 21-day screening period; however, all protocol related procedures must 
only be performed after signing of the consent.  
Demographic/Medical History 
A complete medical history will be taken.  Information to be documented includes 
demographic information (age, gender, ethnicity, and race), prior and ongoing medical 
illnesses and conditions, and surgical procedures (not related to the primary diagnosis).   
Note:  Data will be collected according to local regulations. 
Disease History 
This information should include the date of initial diagnosis, date of most recent relapse, 
staging at study entry, prior anti-cancer therapies (including radiation therapy) and/or 
surgeries, current signs and symptoms of malignant disease, metastatic sites of disease, and 
measurement of target lesions.  For prior antineoplastic treatments, start and end dates of 
treatments, and method by which disease progression was confirmed (eg, CT, MRI). 
IMDC Risk Category 
The IMDC risk category will be determined according to the IMDC criteria (see Appendix H). 
Prior and Concomitant Medications 
Prior medications will be collected at the time of screening.  All concomitant medications will 
be collected from time the subject signs the ICF throughout the subject’s participation in the 
study, including a period of 30 days after their last dose of study drug. 
Adverse Event Assessments 
Refer to Section 12 for information regarding adverse events reporting requirements.  
Eastern Cooperative Oncology Group (ECOG) Performance Status 
Subject’s performance status will be assessed using the ECOG performance status tool (see 
Appendix B). 
Vital Sign Measurements 
Vital sign measurements will be collected after the subject has been sitting for 5 minutes.  
Vital sign assessments will include measurements of diastolic and systolic blood pressure 
(mmHg), heart rate (beats per minute), respiration rate (breaths per minute), and body 
temperature (Celsius). 
Physical Examination 
A complete physical examination (PE) will be performed at screening by a physician or staff 
member who is qualified to perform such examinations (eg, physician’s assistant, or nurse 


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practitioner).  The complete PE will include a thorough review of all body systems and 
include measurements of weight (kg) and height (cm).   
At all other visits throughout the study, a directed PE, including weight (kg), will be 
completed in a targeted manner covering body systems related to the subject’s disease or 
relevant findings in the complete PE performed a the Screening visit.   
Hematology 
Hematology assessments are to include complete blood count (CBC) with differential and 
platelet count.  Hematology evaluations should be increased in frequency in the event of a 
clinically significant hematologic toxicity. 
Serum Chemistries 
Serum chemistry assessments are to include measurements of sodium, potassium, chloride, 
bicarbonate (optional), blood urea nitrogen (BUN), creatinine, glucose, total bilirubin, direct 
bilirubin, AST, ALT, lactate dehydrogenase (LDH), alkaline phosphatase, calcium, 
magnesium, phosphorus, albumin, amylase, lipase, and total protein.  
Thyroid Function Tests 
Thyroid function tests are to include measurements of thyroid stimulating hormone (TSH), 
total T3 (triiodothyronine) (optional), and free T4 (thyroxine).  
Coagulation Parameters 
Coagulation parameter assessments are to include measurements of prothrombin time (PT) 
and/or international normalized ratio (INR), and partial thromboplastin time (PTT).   
Urinalysis  
Urinalysis assessments are to include determinations of protein, glucose, ketones, 
urobilinogen, occult blood, and microscopic sediment evaluation.  A 24-hour urine for protein 
will be performed whenever protein is 4+.
Pregnancy Test 
A serum pregnancy test will be performed on all females of childbearing potential within 
7 days prior to the first dose of study drug.
12-Lead Electrocardiogram (ECG) 
ECGs will be performed after subjects have been supine for approximately 10 minutes.  
Assessment of normal, abnormal, not clinically significant, and abnormal, clinically 
significant (with reason noted) will be collected in the electronic case report form (eCRFs).
Disease/Response Assessment   
Disease and response assessments will be determined using RECIST (Version 1.1, 
Appendix A).  
Disease/response assessment is to include disease classification (including details of the 
primary diagnosis and histological/cytological type and stage of disease at Screening) and 
diagnostic imaging / measurement of lesions.  


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The same method of assessment and the same technique should be used throughout the study.  
CT and MRI will be considered the standard method for evaluating disease status.  All 
subjects should have a CT scan or MRI of the head, chest, abdomen, and pelvis at baseline.  
During subsequent disease/response assessments, a CT scan or MRI of the head will only be 
required if the subject had brain metastasis at baseline or new symptoms suggestive of brain 
metastasis.  The location of target and non-target lesions and dimensions of target lesions will 
be documented on the subject’s eCRF, where such information is available.   
Response assessment and updates will be performed and documented.  Response assessment 
will continue until the time of disease progression or start of another anti-cancer therapy. 
If disease progression is documented at any time, no further imaging or lesion measurements 
will be required.  Diagnostic studies documenting disease response must be available for 
review by the sponsor, if requested. 
In the event of an objective response, the duration of the response will be determined from the 
day the initial response is observed (using screening/baseline images for comparison) to the 
day that progression is observed.  Duration of disease stabilization will also be assessed (see 
Appendix A).  In the case of stable disease (SD), follow-up measurements must have met the 
SD criteria at least once after study entry at a minimal interval of 8 weeks. 
Pharmacokinetics 
Blood samples for the analysis of pharmacokinetic parameters of tivozanib or sorafenib will 
be collected from all subjects.  Samples will be collected at Cycle 1, Day 1- 4 hours post-dose 
and at Cycle 1, Day 15- pre-dose (within 2 hours before dosing). 
Study Drug Administration Diary 
A Study Drug Administration Diary will be provided to the study subjects at the start of each 
cycle.  Diary information will be recorded and/or collected from each subject during study 
visits.  
7.1.1
Screening Visit 
All subjects must provide written informed consent before any protocol-related tests are 
performed.  All screening assessments are to be performed within 21 days prior to first study 
drug dose, unless otherwise specified; all other assessments will be performed prior to dosing 
unless otherwise stated.  At the screening visit, the following procedures and evaluations will 
be performed: 
•
Medical and disease history 
•
Concomitant medications 
•
Adverse event assessments 
•
ECOG performance status 
•
IMDC risk category 
•
Vital sign measurements 
•
Complete PE  


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•
Hematology 
•
Serum chemistries 
•
Coagulation parameters 
•
Thyroid function tests 
•
Urinalysis  
•
Pregnancy test (to be performed within 7 days prior to first study drug dose)
•
12-lead ECG 
•
Disease assessment (CT scan or MRI scan) of head, chest, abdomen, and pelvis – 
may be performed within 30 days prior to first dose
7.1.2
Cycle 1, Day 1 (Baseline) Visit 
At the Cycle 1, Day 1 Visit, the following procedures and evaluations will be performed: 
•
Concomitant medications 
•
Adverse event assessments  
•
Study drug administration 
•
ECOG performance status 
•
Vital sign measurements 
•
Directed PE  
•
Hematology 
•
Serum chemistries 
•
Coagulation parameters 
•
Urinalysis  
•
Pharmacokinetics sample at hour 4 post dose 
•
Distribute study drug diary 
Note:  If ECOG performance status, PE, hematology, serum chemistry, coagulation 
parameters, and urinalysis were measured/performed within 7 days prior to this visit, they 
need not be repeated.
7.1.3
Cycle 1, Day 15 Visit (± 2 days) 
At the Cycle 1, Day 15 Visit, the following procedures and evaluations will be performed: 
•
Concomitant medications 
•
Adverse event assessments  
•
Study drug administration 
•
ECOG performance status 


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•
Vital sign measurements 
•
Directed PE  
•
Hematology 
•
Serum chemistries 
•
Coagulation parameters 
•
Pharmacokinetic sample pre-dose (within 2 hours before dosing) 
•
Urinalysis  
•
Review Study Drug Administration Diary 
7.1.4
Cycle 2, Day 1 Visit (± 2 days) 
At the Cycle 2, Day 1 Visit, the following procedures and evaluations will be performed: 
•
Concomitant medications 
•
Adverse event assessments  
•
Study drug administration 
•
ECOG performance status 
•
Vital sign measurements 
•
Directed PE  
•
Hematology 
•
Serum chemistries 
•
Coagulation parameters 
•
Thyroid function tests 
•
Urinalysis  
•
Review Study Drug Administration Diary from previous cycle 
•
Distribute Study Drug Administration Diary 
7.1.5
Every 8 weeks from Cycle 1, Day 1 (± 3 days) 
Every 8 weeks (± 3 days), the following procedures and evaluations will be performed: 
•
Disease/response assessment (CT scan or MRI scan)   
The assessment should be done during scheduled visits where appropriate and possible. 
7.1.6
Subsequent Cycles – Day 1 Visit (± 2 days) 
At subsequent cycle Day 1 visits, the following procedures and evaluations will be performed: 
•
Concomitant medications 
•
Adverse event assessments  


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•
Study drug administration 
•
ECOG performance status 
•
Vital sign measurements 
•
Directed PE  
•
Hematology 
•
Serum chemistries 
•
Coagulation parameters 
•
Thyroid function tests – every even-numbered cycle beyond Cycle 2 (ie, Cycle 4, 6, 
8, etc)
•
Urinalysis 
•
Review of Study Drug Administration Diary from previous cycle 
•
Distribute Study Drug Administration Diary 
7.1.7
End-of-Treatment 
At the End-of-Treatment Visit, the following procedures and evaluations will be performed up 
to 7 days after last dose of study drug: 
•
Concomitant medications 
•
Adverse event assessments  
•
ECOG performance status 
•
Vital sign measurements 
•
Directed PE  
•
Hematology 
•
Serum chemistries 
•
Coagulation parameters 
•
Thyroid function tests 
•
Urinalysis  
•
Pregnancy test 
•
12-lead ECG 
•
Disease/response assessment (CT scan or MRI scan):  If a subject has already 
undergone a tumor assessment within 30 days prior to the End-of-Treatment Visit 
that shows disease progression as confirmed by IRR, a repeat scan is not necessary 
at the End-of-Treatment Visit. 
•
Review Study Drug Administration Diary 
Note:  Assessments performed within 3 days of the End-of-Treatment Visit need not be repeated.  


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7.1.8
30-Day Follow-Up Visit (± 7 days) 
At the 30-Day Follow-Up Visit, the following procedures and evaluations will be performed: 
•
Concomitant medications 
•
Adverse event assessment 
•
ECOG performance status 
•
Vital sign measurements 
•
Directed PE 
•
Hematology 
•
Serum chemistries 
•
Coagulation parameters 
•
Thyroid function tests 
•
Urinalysis 
•
12-lead ECG 
7.1.9
Unscheduled Visits (To Occur as Needed) 
If additional visits are needed, the following procedures may be obtained/performed/ 
measured as clinically indicated: 
•
Concomitant medications 
•
Adverse event assessments  
•
ECOG performance status 
•
Vital sign measurements 
•
Directed PE  
•
Hematology 
•
Serum chemistries 
•
Coagulation parameters 
•
Thyroid function tests 
•
Urinalysis  
•
Review Study Drug Administration Diary 
•
Pregnancy Test 
•
12-Lead ECG 
•
Disease/Response assessment (CT scan or MRI scan) 


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7.1.10
Long Term Response and Survival Follow-Up 
•
All subjects will be followed until death from any cause (unless the subject is lost 
to follow-up, withdraws consent for the entire study, or the Sponsor terminates the 
study early).  After the 30-Day Follow-up visit, subjects will be contacted once 
every 3 months by the site to collect long-term survival data.  Additional contacts 
may be made to support key analyses, such as the analysis of overall survival at the 
time of the final PFS analysis, and the final analysis of overall survival.   
•
Response assessment (CT scan or MRI scan):  for subjects with ongoing objective 
response or disease stabilization at the time of treatment discontinuation, who 
discontinue for reasons other than radiological evidence of progressive disease, 
tumor assessments will continue to be collected (every 2 months during the first 
year [beginning from the date of the last scan performed prior to treatment 
discontinuation], every 3 months during the second year, and every 6 months 
thereafter) until disease progression is confirmed by independent radiology review 
or the start of another anti-cancer therapy (see Section 7.2.4). 
7.2
Study Drug Administration 
7.2.1
Tivozanib Administration 
Tivozanib will be administered orally, at a dose of 1.5 mg/day, beginning on Day 1 of 
Cycle 1.  Subjects will receive tivozanib once daily for 3 weeks followed by 1 week off study 
drug (1 cycle = 3 weeks on, 1 week off).  One cycle will be defined as 4 weeks of treatment.  
Cycles will be repeated every 4 weeks. 
The prescribed daily dose of tivozanib is to be taken, preferably in the morning, with water.  
Tivozanib should be taken at least 1 hour before or 2 hours after ingesting any food or other 
medications.  Grapefruit juice should not be ingested during the study.  On days of a 
scheduled clinic visit, the dose of tivozanib should be taken at the clinic after visit procedures 
are completed.  Treatment with tivozanib will continue if tolerated and in the absence of 
documented disease progression.  If a dose is vomited or if a dose is missed for any reason, 
the dose should not be made up.  If Day 1 of a cycle is delayed for any reason, the complete 
21 days of tivozanib should be administered once the cycle is started.  Only one tivozanib 
capsule should be taken each day. 
7.2.2
Sorafenib Administration 
Sorafenib will be administered orally, at an initial dose of 400 mg twice daily continuously, 
beginning on Day 1 of Cycle 1.  One cycle will be defined as 4 weeks of treatment.  Cycles 
will be repeated every 4 weeks.  
Sorafenib should be taken without food at least 1 hour before or 2 hours after ingesting any 
food or other medications.  On days of a scheduled clinic visit, the dose of sorafenib should be 
taken at the clinic after visit procedures are completed.  Treatment with sorafenib will 
continue if tolerated and in the absence of documented disease progression.  If a dose is 
vomited or if a dose is missed during a cycle for any reason, the dose should not be made up.  
If Day 1 of a cycle is delayed for any reason, the complete 28 days of sorafenib should be 
administered once the cycle is started. 


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7.2.3
Review of Safety Data During Study 
The investigator(s) and medical monitor(s) will review safety data on an ongoing basis 
throughout the study and make decisions regarding the advisability of continuing accrual to 
the study.  In order to do so, the following will occur:   
•
All serious adverse events (SAEs) must be reported to the sponsor within 24 hours 
of the investigator becoming aware of the SAE (see Section 12.3, Serious Adverse 
Events).   
•
The Adverse Events pages of the subject’s eCRF should be promptly completed 
(ie, within 2 weeks) of a subject’s visit (or being discontinued from the study).  
7.2.4
Duration of Study Treatment  
Subjects with documented stable disease or an objective response may continue to receive 
therapy at the same dose and schedule until disease progression or unacceptable toxicities 
occur, or if other withdrawal criteria are met, as outlined in Section 11.1.
Discontinuation:  Subjects experiencing unacceptable toxicities will be discontinued from 
further study treatment.  Subjects with radiological evidence of progressive disease (per 
RECIST Version 1.1) per investigator/local radiology assessment should continue treatment 
until progressive disease is verified by an independent radiologist.  Images should be 
submitted for independent review as soon as possible (see Imaging Manual for specific 
instructions).  Verification of progressive disease is not required in the following 
circumstance: 
•
Significant clinical deterioration that is compatible with progressive disease.  
Subjects who have documented disease progression (as verified by an independent 
radiologist) will be discontinued from the study treatment. 
7.2.5
Duration of Follow-Up 
Follow-up safety evaluations will be conducted 30 days following the subject’s last dose of 
study drug.  This period will be extended if any observed toxicity, thought to be associated 
with study drug, has not resolved or returned to baseline.  
Note:  The occurrence of any significant post-therapy event thought to be associated with study drug must be 
reported to the sponsor.  
Subjects starting any new anti-cancer therapy must complete the End-of-Treatment Visit prior 
to starting the new anti-cancer therapy.  Adverse Event Assessment will be conducted in order 
to confirm that all events have resolved, stabilized, or returned to baseline and that no 
longer-term deleterious effects of study drug administration have become evident.  
In the event that a subject has an ongoing objective response or disease stabilization at the 
time of treatment discontinuation, who discontinues for reasons other than radiological 
evidence of progressive disease (per RECIST Version 1.1, as confirmed by independent 
radiology review), tumor assessments will continue to be collected (every 2 months during the 
first year [beginning from the date of the last scan performed prior to treatment 
discontinuation], every 3 months during the second year, and every 6 months thereafter) until 
disease progression (per RECIST Version 1.1) is confirmed by independent radiology review 


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the start of another anti-cancer therapy, or discontinuation of the subject from overall study 
participation (ie, death, subject withdrawal of consent, or loss to follow-up, or study closure).   
After discontinuation from all study treatment, follow-up information for long-term survival 
and subsequent anti-cancer therapy, if available, will be obtained every 3 months from the 
End of Treatment Visit or 30-Day Follow-up Visit (whichever is later) until death, withdrawal 
of consent, loss to follow-up, or study closure, whichever occurs first.  Additional contacts 
may be made to support key analyses, such as the analysis of overall survival at the time of 
the final PFS analysis, and the final analysis of overall survival.  
7.3
Prior and Concomitant Medications 
All concomitant medications or medication administered will be collected from the time the 
subject signs the ICF throughout their participation in the study, including a period of 30 days 
after last dose of study drug.  These data must be recorded on the appropriate eCRF along 
with the indication for which it was used.  The generic name of the drug must be specified 
along with the start date, stop date, and route of administration.  Additionally, any diagnostic, 
therapeutic, or surgical procedure performed during the study period must be recorded on the 
eCRF, including the date, indication, description of the procedure(s) and any clinical finding. 
Any medication considered necessary for the subject’s welfare, and which is not expected to 
interfere with the evaluation of the study drug, may be given at the discretion of the 
investigator.  Drugs and treatment specifically excluded are described in Section 6.3, Drugs 
and Other Treatments to be Excluded. 
7.4
Randomization and Blinding 
The IWRS will be used for randomization and drug management (packaging of clinical 
supplies, shipping to study sites, and dispensing to subjects). 
Subjects will be randomized in a 1:1 ratio (tivozanib: sorafenib) stratified by IMDC risk 
category (favorable; intermediate; poor) and prior therapy (two prior VEGFR TKIs; a prior 
checkpoint inhibitor [PD-1 or PD1 L inhibitor] plus a prior VEGFR TKI; a prior VEGFR TKI 
plus any other systemic agent). Once the strata have been identified, treatment will be 
randomly assigned to a subject within the strata using a complete permuted block design, in 
an unblinded fashion (open-label).  In the event a subject had both 2 TKIs and a checkpoint 
inhibitor, the subject will be stratified according to the most recent line of therapy. 
Subjects must begin treatment with study drug within 14 days after randomization. 
8
STUDY DRUG MATERIALS AND MANAGEMENT 
For purposes of this study, “study drug” will refer to either tivozanib or sorafenib.  Complete 
study drug information (packaging, labeling, storage, disposition, etc.) is provided in 
Appendix F, Tivozanib Study Drug Information and Appendix E, Sorafenib Prescribing 
Information. 
All study drug information will be recorded on the Drug Dispensing Log or other appropriate 
study drug inventory.  This inventory will be maintained throughout the duration of the study 
and will be periodically reviewed by a representative of the sponsor.  


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8.1
Study Drug 
Prior to the start of the study, the sponsor will provide labeled supplies of tivozanib to the 
study center investigational pharmacy.  Tivozanib is formulated for oral administration as a 
white opaque number 4 gelatin capsule containing 1.0 or 1.5 mg tivozanib.  Sorafenib is 
formulated for oral administration as a round, biconvex, red film-coated tablet, debossed with 
the “Bayer cross” on one side and “200” on the other side.  
8.2
Study Drug Packaging and Labeling 
Tivozanib will be packaged and labeled by the sponsor according to all local legal 
requirements.  Tivozanib will be labeled in accordance with applicable regulatory 
requirements. 
8.3
Study Drug Shipment 
Study drug will be shipped to the site via Randomization and Trial Supply Management 
system after the first subject has been screened, instead of after site activation or a site 
initiation visit. Exceptions to this process will be allowed after careful review by the sponsor. 
8.4
Dispensing of Study Drug and Dosing Compliance 
The amount of study drug dispensed to the subject at the beginning of each dosing cycle will 
be sufficient to allow for 3 weeks (21 days) of consecutive once-daily dosing of tivozanib or 
4 weeks (28 days) of consecutive twice-daily dosing of sorafenib. 
•
The investigator (or designee) will be responsible for determining the amount of 
drug and the appropriate dosage strength to dispense to the subject at the beginning 
of each cycle.   
•
The investigator (or designee) will be responsible for recording this information on 
the Drug Dispensing Log or other appropriate study drug inventory.  This 
inventory will be maintained throughout the duration of the study and will be 
periodically reviewed by a representative of the sponsor. 
The investigator (or designee) will instruct the subject that all dispensed pill bottles must be 
returned at each follow-up visit, at which time a tablet/capsule count will be conducted to 
assure subject dosing compliance. 
8.5
Study Drug Storage 
Tivozanib does not have any special storage requirements, and may be stored at room temperature in a 
dry place, in a secure location.  Sorafenib is to be stored at room temperature (15°–25° C) in a dry 
place, in a secure location.
8.6
Study Drug Accountability 
The US Food and Drug Administration (FDA) and other regulatory agencies require 
accounting for the disposition of all investigational drugs received by each clinical site.  
Information on drug disposition required by law consists of the date received, date 
administered, quantity administered, and the subject to whom the drug was administered.  The 
principal investigator is responsible for the accounting for all unused study drugs and all used 


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study drug containers.  The investigator must maintain a complete and current dispensing and 
inventory record that has been supplied by the sponsor. 
8.7
Study Drug Handling  
At the termination of the study, a final drug accountability review and reconciliation must be 
completed and any discrepancies must be investigated and their resolution documented. 
8.7.1
Disposition of Used Supplies 
At the completion of a subject’s participation in the study, all partially used and empty pill 
bottles must be returned to the investigator (or designee) so that a final subject-dosing 
inventory may be conducted.  This information will be recorded on the Drug Dispensing Log.  
8.7.2
Inventory of Unused Supplies 
Periodically throughout and at the conclusion of the study, an inventory of unused bottles of 
study drug will be conducted by a representative of the sponsor.   
9
ASSESSMENT OF ACTIVITY 
9.1
Disease Classification and Response Assessments  
Data on disease classification and the duration of disease stabilization or any objective 
response, as well as the time to disease progression, will be collected for all subjects.  Subjects 
will undergo disease assessment at screening (within 30 days prior to first dose of study drug) 
and every 8 weeks following Cycle 1, Day 1 until radiological disease progression is 
documented and confirmed by independent radiology review. Response will be determined by 
RECIST (Version 1.1) criteria (Appendix A).   
Disease parameters to be assessed: 
•
Disease classification 
•
Diagnostic imaging/measurement of target lesions 
•
Response assessment.  
Disease Classification 
Details of the primary diagnosis should be documented at the Screening Visit.  The 
histological/cytological type and stage of disease should be noted on the eCRF. 
Diagnostic Imaging/Measurement of Lesions 
Subjects should be followed with the same imaging procedure throughout this study; if 
progressive disease (PD) is documented at any time per RECIST Version 1.1, no further 
imaging or lesion measurements will be required after PD is verified by an independent 
radiologist; diagnostic studies documenting response must be available for sponsor review. 
Response Assessment  
Response will be assessed as detailed in Appendix A using RECIST criteria Version 1.1.  All 
subjects who receive a minimum of 2 cycles of study drug will be considered evaluable for 
response assessment.  All subjects who develop early progressive disease (regardless of the 


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duration of the study treatment) prior to response evaluation will be considered to have 
progressed on study. 
The duration of any objective response is to be measured from the date the initial response is 
observed to the date that disease progression is observed.  In the case of SD, follow-up 
assessments must have met the SD criteria at least once after study entry, at a minimal interval 
of 8 weeks.  
Response Assessment Update 
In the event that a subject has an ongoing objective response or disease stabilization at the 
time of treatment discontinuation, who discontinue for reasons other than radiological 
evidence of progressive disease, tumor assessments will continue to be collected (every 
8 weeks during the first year, every 3 months during the second year, and every 6 months 
thereafter) until disease progression is confirmed by independent radiology review or the start 
of another anti-cancer therapy.  Data will continue to be collected on the duration of objective 
response or disease stabilization, as well as on the overall time to disease progression until the 
subject experiences disease progression as confirmed by independent radiology review, or 
starts another anti-cancer therapy. 
10
MANAGEMENT OF TOXICITY 
Comprehensive assessments of any toxicity experienced by the subject will be performed 
throughout the course of this study.  Anticipated toxicities that may be experienced are 
detailed in Section 3.1, Background; Section 13, Precautions; and in the Investigator’s 
Brochure (IB).  Grades of toxicity (NCI Common Terminology for Adverse Events [CTCAE 
Version 4.03]), as well as clinical judgment, will be used to determine appropriate 
management of the subject experiencing any adverse event while participating in this study. 
10.1
Grading and Recording of Toxicity 
Any significant clinical adverse event, whether observed by the investigator, or observed or 
experienced by the subject, will be reported.  Any clinically significant change from baseline 
in a laboratory parameter will be reported as an adverse event.  All clinical and laboratory 
adverse events must be carefully evaluated for the following minimum criteria: 
•
Severity (see Appendix G; mild, moderate, severe, life-threatening, fatal)* 
•
Duration 
•
Relationship to study drug (Yes / No).  
*Note:  In cases for which further definition of an event is provided by the NCI Common Terminology 
Criteria for Adverse Events Version 4.03, please refer to this document for grading and severity 
information.  
This information is to be documented on the appropriate page of the eCRF. 
10.2
Evaluation and Treatment of Toxicity 
The principal investigator, sub-investigator, or designated health professional must be 
available throughout the course of the study in order to evaluate and treat any adverse 


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event(s), as well as to evaluate whether continued participation in the study is warranted or 
advisable.  
If, at any point during the study, significant changes occur in either the subject’s clinical status 
or laboratory parameters, such changes will be followed until the parameter(s) either returns to 
baseline or is adequately explained. 
10.3
Management of Skin Toxicities (Sorafenib) 
Management of skin toxicity associated with sorafenib is outlined in Table 3.  Please refer to 
sorafenib prescribing information for additional information (see Appendix E).   
Table 3: 
Management of Skin Toxicity Associated with Sorafenib 
Skin Toxicity Grade 
Occurrence 
Suggest Dose Modification 
Grade 1:  Numbness, dysesthesia, 
paresthesia, tingling, painless swelling, 
erythema or discomfort of the hands or feet 
which does not disrupt the patient’s normal 
activities 
Any occurrence 
Continue treatment with sorafenib and 
consider topical therapy for symptomatic 
relief 
Grade 2:  Painful erythema and swelling of 
the hands or feet and/or discomfort 
affecting the patient’s normal activities 
First occurrence 
Continue treatment with sorafenib and 
consider topical therapy for symptomatic 
relief 
If no improvement within 7 days, see 
below. 
No improvement 
within 7 days or 
second or third 
occurrence 
Interrupt sorafenib treatment until 
toxicity resolves to Grade 0–1 
When resuming treatment, decrease 
sorafenib dose by one dose level. 
Fourth occurrence 
Discontinue sorafenib treatment.  
Continue follow-up with regular tumor 
assessments until disease progression or 
start of new treatment, and for survival 
thereafter. 
Grade 3:  Moist desquamation, ulceration, 
blistering or severe pain of the hands or 
feet or severe discomfort that causes the 
patient to be unable to work or perform 
activities of daily living 
First or second 
occurrence 
Interrupt sorafenib treatment until 
toxicity resolves to Grade 0–1 
When resuming treatment, decrease 
sorafenib dose by one dose level 
(400 mg daily or 400 mg every other 
day) 
Third occurrence 
Discontinue sorafenib treatment.  
Continue follow-up with regular tumor 
assessments until disease progression or 
start of new treatment, and for survival 
thereafter. 
10.4
Study Drug Administration Modification 
Clinical judgment will be used to determine appropriate management of the subject during 
any AE.  The criteria for dose modification for drug-related AEs (excluding hypertension and 


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skin toxicity) are summarized in Table 4. Further management is at the discretion of the 
investigator, who may discuss this with the medical monitor if necessary. 
Table 4: 
Dose Modification Guidelines for Drug-Related Adverse Events 
Drug-Related Adverse Events 
(excluding Hypertension1 and 
Skin Toxicity2) 
Intervention 
Grade 1 
Continue treatment at same dose 
Grade 2 
Continue treatment at same dose 
Grade 3 
Decrease dose (see Section 10.4.2 for tivozanib and Section 10.4.3 for 
sorafenib dose reduction guidelines) 
Grade 4 
Interrupt dosing; restart at lower dose as soon as toxicity improves to 
≤ Grade 2 (see Section 10.4.1 for tivozanib and Section 10.4.3 for 
sorafenib dose reduction guidelines) 
1 Hypertension must be treated as described in Section 10.4.1 prior to dose modification 
2 Skin toxicity should be managed as described in Section 10.2 
10.4.1
Tivozanib Dose Reduction 
Dose reductions of tivozanib to 1.0 mg/day will be allowed for subjects with ≥ Grade 3 
drug-related adverse events.  The exception is hypertension, which must be treated with 
anti-hypertensive drugs (see Appendix D) prior to dose reduction.   
The dose of tivozanib may be reduced to 1.0 mg/day.  Once the dose of tivozanib is reduced, 
it may not be re-escalated throughout the study.  If a subject is unable to tolerate a dose of 
1.0 mg/day due to toxicities thought to be related to tivozanib, dosing with tivozanib should 
be discontinued.  
Any modification of study drug administration, and the reason for such action, must be clearly 
noted on the subject’s eCRF using the Adverse Events reporting page.   
10.4.2
Tivozanib Dose Interruption 
Subjects with Grade 4 drug-related toxicity, or Grade 3 drug-related toxicity that is persistent 
despite appropriate medical care, should have their dose interrupted to allow for resolution of 
the toxicity.  Tivozanib may be interrupted for up to 4 weeks.  If a subject is able to resume 
treatment after interruption of ≤ 4 weeks, missed doses will not be made up (ie, cycle duration 
will remain unchanged).  If any drug-related toxicity results in interruption of > 4 weeks, the 
subject should be discontinued from the study unless there is clear benefit from treatment, in 
which case the investigator must contact the medical monitor to review the subject’s condition 
in order to resume treatment.  Subjects removed from treatment for reasons other than 
radiological evidence of progressive disease should still be followed with regular tumor 
assessments (see Section 7.2.4) until disease progression is confirmed by independent 
radiology review or start of new treatment, and for survival thereafter.   


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Any modification of study drug administration, and the reason for such action, must be clearly 
noted on the subject’s eCRF using the Adverse Events reporting page). 
10.4.3
Sorafenib Dose Reduction 
Dose modification will be allowed for subjects with ≥ Grade 3 drug-related adverse events.  
Skin toxicity associated with sorafenib should be managed as shown in Section 10.2, 
Management of Skin Toxicities (Sorafenib), prior to dose reduction.  The dose of sorafenib 
will be reduced to 400 mg once daily.  If toxicities do not resolve, sorafenib may be further 
reduced to 400 mg once every other day.  If a subject is unable to tolerate a dose of 400 mg 
once every other day due to toxicities thought to be related to sorafenib, treatment should be 
interrupted.  If toxicities resolve to ≤ Grade 1, the dose may be re-escalated to the previous 
dose level at the discretion of the investigator.  For management of specific sorafenib-related 
toxicities, please refer to the sorafenib prescribing information (Appendix E). 
Any modification of study drug administration, and the reason for such action, must be clearly 
noted on the subject’s eCRF (using the Adverse Events reporting page). 
10.4.4
Sorafenib Dose Interruption 
Subjects with Grade 4 toxicity, or Grade 3 drug-related toxicity that is persistent despite dose 
reduction and appropriate medical care, should have their treatment interrupted to allow for 
adequate resolution of the toxicity.  Sorafenib may be interrupted for up to 4 weeks.  If a 
subject is able to resume treatment after interruption of ≤ 4 weeks, missed doses will not be 
made up (ie, cycle duration will remain unchanged).  If any drug-related toxicity results in 
interruption of > 4 weeks, the subject should be discontinued from the study unless there is 
clear benefit from treatment, in which case the investigator must contact the medical monitor 
to review the subject’s condition in order to resume treatment. Subjects removed from 
treatment for reasons other than radiological evidence of progressive disease should still be 
followed with regular tumor assessments (see Section 7.2.4) until disease progression is 
confirmed by an independent radiology review or start of new treatment, and for survival 
thereafter. 
11
REMOVING SUBJECTS FROM STUDY 
Every reasonable effort will be made to keep the subject in the study; however, in the event 
that a subject withdraws consent from study participation, every effort will be made by the 
investigator to complete and report the reasons for withdrawal as thoroughly as possible.  This 
evaluation should include final observations, as required by the protocol at the time of the 
subject’s withdrawal.  The reason(s) for study termination must be clearly documented in the 
source documents and on the appropriate page of the eCRF.  A Termination eCRF must be 
completed for any subject who is randomized.   
11.1
Criteria for Treatment Discontinuation (Stopping Rules) 
Subjects will be discontinued from further treatment with study drug in the event of any of the 
following:  
1. Death 
2. Unacceptable toxicity considered by the investigator to require removal of the subject 
from study treatment. 


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Note:  Adverse events resulting in a subject’s permanent discontinuation from the study treatment, 
regardless of seriousness or relationship to study drug, MUST be promptly reported to the 
sponsor/designee.  Subjects removed from treatment for intolerable toxicity should still be followed 
with regular tumor assessments (see Section 7.2.4) until disease progression or start of new 
treatment, and for survival thereafter.   
3. Documented progressive disease according to RECIST Version 1.1 at any time during 
the study.   
4. Subjects with radiological evidence of progressive disease per investigator/local 
radiology assessment should continue treatment until progressive disease is verified by 
an independent radiologist.  Images should be submitted for independent review as 
soon as possible (see Imaging Manual for specific instructions).  Verification of 
progressive disease is not required in the following circumstance: 
•
Significant clinical deterioration that is indicative of progressive disease. 
5. Subjects who have documented disease progression will be discontinued from study 
drug treatment and will continue to be followed up for survival.   
6. Clinical progression (eg, symptomatic deterioration) not meeting the RECIST 
Version 1.1 criteria for radiological evidence of progressive disease but considered by 
the investigator to require removal of the subject from study.  This includes subjects 
with significant clinical deterioration that is indicative of progressive disease.  All 
related signs and symptoms of clinical progression must be captured in AE eCRF 
page, the term “progressive disease” should not be recorded as an adverse event or 
captured on the eCRF page.  
7. Treatment interruption for > 4 weeks (ie, total duration of interruption, including the 
1 week/cycle break in dosing of tivozanib), unless there is clear benefit from 
treatment, in which case the investigator must contact the medical monitor to review 
the subject’s condition in order to resume treatment. 
8. Requirement for a significant surgical procedure.   
Note:  Subjects requiring a minor surgical procedure (eg, port placement, skin abscess drainage) 
may continue on study at the investigator’s discretion following discussion with the medical 
monitor.  A brief interruption in therapy (< 4 weeks) may be considered. 
9. An intercurrent illness which, in the opinion of the investigator, would prevent 
completion of study-related evaluations. 
10. Significant deviation from the protocol or eligibility criteria.  Such subjects will be 
considered protocol violations and will be removed from study unless there is an 
exemption granted that is agreed upon between the investigator and the sponsor.  
11. Pregnancy. 
12. Noncompliance with study or follow-up procedures. 
13. Subject withdrawal of consent and election to discontinue the study treatment. 
Note: The subject is free to withdraw from the study drug and/or study for any reason and at any 
time without giving reason for doing so and without penalty or prejudice.  In the event of consent 
withdrawal, the site should make every effort to ensure that the subject is followed for AEs for a 


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minimum of 30 days after their last dose of study treatment.  With documented subject agreement, 
the investigator will contact the subject for long-term survival follow-up.
14. Termination of the study by the sponsor. 
15. Any other reason which, in the opinion of the investigator, would justify removing the 
subject from the study.  In such a case, the investigator’s reason for a subject’s 
removal must be recorded on the appropriate eCRF. 
Once a subject discontinues study drug treatment for any reason, every effort will be made to 
collect all clinical and laboratory data as scheduled for the End-of-Treatment Visit and 
30-Day Follow-up Visit (see Section 7.1.7 and Section 7.1.8) as well as long term response 
and survival follow-up (Section 7.1.10). 
Subjects who are discontinued from study drug for reasons other than progression by RECIST 
Version 1.1 will undergo scans for tumor assessment according to the original tumor 
assessment schedule until any of the following occurs, whichever comes first:  PD per 
RECIST Version 1.1 (as confirmed by independent radiology review), initiation of new 
anti-cancer treatment, or discontinuation of the subject from overall study participation (death, 
subject withdrawal of consent, loss to follow-up, or study closure). 
12
ADVERSE AND SERIOUS ADVERSE EVENTS 
Information regarding the occurrence of AEs will be collected from the time the subject signs 
the ICF throughout their participation in the study, including a period of 30 days after last 
dose of study drug (data on SAEs will be collected until resolution of the event unless 
otherwise noted).   
All SAEs must be reported to the Sponsor, as delineated in Section 12.3 of this 
protocol, within 24 hours of the Investigator becoming aware of the event.
12.1
Definition of Adverse Events 
An AE is defined as any untoward medical occurrence in the form of signs, symptoms, 
abnormal laboratory findings, or diseases that emerges or worsens relative to baseline, during 
a clinical study with a study drug, regardless of causal relationship and even if no study drug 
has been administered. 
AEs may include the following types of occurrences: 
•
Suspected adverse drug reactions; 
•
Other medical experiences, regardless of their relationship with the study drug, 
such as injury, surgery, accidents, extensions of symptoms or apparently unrelated 
illnesses, and significant abnormalities in clinical laboratory values or vital signs, 
psychological testing or physical examination findings; 
•
Reactions from study drug overdose, abuse, withdrawal, sensitivity, toxicity or 
failure of the study drug’s expected pharmacological action. 
In cases of surgical or diagnostic procedures, the condition/illness leading to such a procedure 
is considered as the AE rather than the procedure itself.   
In case of a fatality, the cause of death is considered as the AE and the death as its outcome.  


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12.1.1
Abnormal Laboratory Findings and Other Objective Measurements 
Abnormal laboratory findings or other objective measurements that meet the criteria for a 
SAE (see Section 12.3) result in discontinuation of the study drug, require medical 
intervention or are judged by the Investigator to be clinically significant changes from 
baseline values should be captured and reported on the AE pages of the eCRF.  
12.1.2
Medical History 
Medical conditions present at the initial study visit are defined as medical history, and are 
NOT to be considered AEs.  These medical conditions should be adequately documented on 
the medical history page of the eCRF.  However, medical history conditions, other than the 
disease under study, that worsen in severity or frequency during the study and are considered 
clinically significant by the Investigator should be recorded and reported as AEs.  
12.1.3
Exacerbation of Primary Malignancy 
In this protocol, symptoms and signs of exacerbation or worsening of primary malignancy 
will usually be captured in the context of efficacy assessment, and recorded on the pages of 
the appropriate eCRF.  Therefore, symptoms, or signs of exacerbation or worsening of the 
primary malignancy will not be considered as AEs nor captured on the AE page of the eCRF 
unless the event is considered possibly or probably related to the study drug (ie, the worsening 
is not consistent with the anticipated natural progression of the disease), or the subject is 
discontinued from study drug due to clinical progression without documented progressive 
disease.  In this case the events suggesting clinical progression should be recorded in the 
eCRF. 
12.2
Evaluating Adverse Events 
Data on AEs will be obtained at scheduled or unscheduled study visits, based on information 
spontaneously provided by the subject and/or through questioning of the subject.  To elicit 
AEs, questioning at each study visit should begin with simple non-leading questions.  For 
example: 
•
How have you felt since your last visit? 
•
Have you had any health problems since you were here last? 
If a subject is seen by a physician not involved with the study in relation to an AE, the 
Investigator should make every effort to contact the treating physician in a timely manner in 
order to obtain all information necessary to appropriate reporting of the event.  
The Investigator is required to grade the severity/intensity of each AE according to the 
National Cancer Institute - CTCAE, Version 4.03.  A general grading (severity/intensity) scale 
is provided at the beginning of the NCI-CTCAE document, and specific event grades are also 
provided.  If a particular AE’s severity/intensity is not specifically graded by the guidance 
document, the Investigator is to revert to the general definitions of Grade 1 through Grade 5 
and use his or her best medical judgment.  
Note:  Death is mainly regarded as an outcome and should be documented as described below. 
12.3
Serious Adverse Events (SAE)  
(Notify sponsor or designee within 24 hours; document on eCRF) 


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Any SAE requires expedited reporting to the Sponsor’s Pharmacovigilance department, 
regardless of its relationship to the study drug. 
An SAE is defined as an AE that at any dose: 
•
Results in death – ie, the AE causes or contributed to the death of the subject. 
•
Is life threatening – ie, the AE places the subject at immediate risk of death; the 
definition does not apply to an AE that hypothetically might cause death if it were 
more severe. 
•
Requires or prolongs inpatient hospitalization - ie, the AE requires at least a 
24-hour inpatient hospitalization or prolongs a hospitalization beyond the 
expected length of stay. 
o
Hospital admissions for surgery planned before study entry, for social 
reasons or for normal disease management (including treatment 
adjustment) is not to be considered as an SAE according to this criterion. 
o
Elective hospitalizations to simplify trial treatment or trial procedures (eg, 
an overnight stay to facilitate chemotherapy and related hydration therapy 
application) are not considered as SAEs.  However, all events leading to 
unplanned hospitalizations or unplanned prolongation of an elective 
hospitalization (eg, undesirable effects of any administered treatment) must 
be documented and reported as SAEs. 
•
Is a congenital anomaly or birth defect - ie, an adverse outcome in a child or 
fetus of a subject exposed to the study drug before conception or during 
pregnancy.   
•
Results in persistent or significant disability or incapacity - ie, the AE resulted 
in a substantial disruption of the subject’s ability to conduct normal activities. 
•
Is a medically important condition 
Such an event may not be immediately life threatening or result in death or 
hospitalization, but is clearly of major clinical significance.  The AE may 
jeopardize the subject or require intervention to prevent a serious outcome. 
For the purposes of reporting, any suspected transmission of an infectious agent via a study 
drug is also considered a serious adverse reaction and all such cases should be reported in an 
expedited manner as described above. 
12.4
Protocol-Related Adverse Events 
AEs that are not study drug-related may nevertheless be considered by the Investigator or the 
Medical Monitor to be related to the conduct of the clinical study.  That is, the event may be 
related to the fact that a subject is participating in the study.  For example, a protocol-related 
AE may be an event that occurs that is related to a procedure required by the protocol. 


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12.5
Reporting Period 
AEs are collected on an ongoing basis from the time of signature of the written informed 
consent until 30 days after the last dose of study drug.  All subjects who took at least 1 dose of 
study drug should be followed until 30 days after the last dose of study drug.  
It is important that each reported AE (including SAEs) be accurately recorded on the AE page 
of the subject’s eCRF.  An AE report includes a description of the event, whether it is 
considered serious (and if so the criterion satisfied), its duration (onset and resolution dates), 
its severity (graded using a 5-point scale), its relationship to the study drug as assessed by the 
Investigator, any other potential causality factors (if known), any method of treatment given 
or other action taken (including dose modification or discontinuation of the study drug) and its 
outcome.  
New AEs and changes in ongoing AEs or those with an unknown outcome must be recorded 
until 30 days after the last dose of study drug.  
However, any SAE or medically relevant AE that has an ongoing or unknown outcome (as 
determined by the Medical Monitor and Sponsor’s Pharmacovigilance department), will be 
followed until resolution or stabilization under the responsibility of the Sponsor’s 
Pharmacovigilance department.  Beyond the 30-Day Follow-up Visit period, data regarding 
any new, unsolicited, SAE spontaneously reported to the Sponsor by the Investigator will be 
collected and processed by the Sponsor’s Pharmacovigilance department within the Safety 
Database, rather than within the Clinical Database.  SAEs occurring after the 30-Day 
Follow-up Visit, which are assessed as related to study drug, should be reported to the 
Sponsor.   
If a subject is documented as lost to follow-up, no further attempt will be made to follow up 
on ongoing AEs or AEs of unknown outcome.  
For screening failure subjects, new SAEs and changes in SAEs will be monitored from the 
signing of the informed consent until the date the subject was determined to be a screening 
failure.  Beyond that date, SAEs which occurred between the signing of informed consent and 
determination of screen failure will be followed-up by the Sponsor’s Pharmacovigilance 
department.  
12.6
Reporting Serious Adverse Events and Subject Deaths 
12.6.1
Timeframe for Reporting 
The Investigator must notify the Sponsor (or their designee) within 24 hours of becoming 
aware of a new SAE or of new (follow-up) information on a previously reported SAE.  
To do so, the Investigator/Reporter must complete an SAE Report Form as detailed in the 
SAE Report Completion Instructions.  The SAE Report Form will be transmitted by the 
Investigator/Reporter to the Sponsor’s Pharmacovigilance department/designee for this study.  
12.6.2
Reporting of Subject Death 
The death of any subject after date of ICF signing and within 30 days of last dose of study 
drug, regardless of the cause, must be reported by the Investigator or qualified designee to the 
Sponsor within 24 hours of the day of first becoming aware of the death.  Deaths occurring 
after the 30-day period do not need to be reported as SAEs for this study (however, deaths 


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occurring at any time after the 30-day follow-up period and which are assessed as related to 
study drug should be reported to the Sponsor as SAEs).  If the report is given via telephone 
rather than in writing on the form designated for SAE reporting, a full description of the 
circumstances, including the Investigator-determined causality in relation to the study drug 
must be provided, so that the appropriate written report can be completed by the designated 
Sponsor contact.   
Reports of all deaths must also be communicated as soon as possible to the appropriate IRB or 
EC and/or reported in accordance with local law and regulations. 
12.6.3
Reporting of Overdose 
An overdose of tivozanib or sorafenib is higher than the intended dispensed dose.  
Information on overdoses in clinical subjects is collected by the Sponsor's Drug Safety 
Surveillance department.  Should a subject experience an overdose during the course of the 
study (whether symptomatic or not), the investigator or qualified designee must report to the 
Sponsor within 5 working days of the investigator or qualified designee first becoming aware 
of the overdose.  Follow-up information on the outcome of the overdose should be forwarded 
to the Sponsor.  
Any event associated with, or observed in conjunction with, a product overdose (whether 
accidental or intentional) or a product abuse and/or withdrawal is considered an AE and 
should be reported as such (see Sections 12.1-12.5).  If a serious adverse event occurs in 
conjunction with the overdose, then the reporting time frame for an SAE (1 working day of 
first becoming aware of the event) must be met.  The Sponsor will provide instructions on 
how to collect this information.  
12.6.4
Reporting to the Institutional Review Board/Ethics Committee 
The Investigator must comply with any applicable requirements related to the reporting of 
SAEs involving his/her subjects to the IRB/EC that approved the study.  In particular, all 
deaths must be promptly reported to the IRB/EC that approved the study.  
In accordance with International Conference on Harmonisation (ICH) Good Clinical Practice 
(GCP) guidelines, the Sponsor will inform the Investigator of “findings that could affect 
adversely the safety of subjects impact the conduct of the study or alter the IRB/EC’s 
approval/favorable opinion to continue the study.”  In line with respective regulations and 
Sponsor’s policy, the Sponsor will inform the Investigator of adverse events that are both 
serious and unexpected and are considered to be possibly or probably related to the study drug 
by the Investigator/Reporter.  The Investigator will keep copies of these safety reports in the 
Investigator file.  National regulations with regards to Safety Report notifications to 
Investigators will be also taken into account.  
Unless clearly defined otherwise by national or site-specific regulations, and duly documented, 
the responsible Investigator will promptly notify the concerned IRB/EC of any Safety Reports 
provided by the Sponsor and provide copies of all related correspondence to the Sponsor.  The 
Sponsor will provide appropriate Safety Reports directly to the concerned IRB/EC and 
maintain records of these notifications only when specifically required by regulations.  


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12.6.5
Information to be Provided by the Investigator 
For any new SAE, the initial notification must include the following information at a 
minimum: 
•
Clear identification of the Investigator/Reporter with full contact information. 
•
Subject identification details (study number, site number, initials, date of birth). 
•
Study drug administration details (dose and dates). 
•
Diagnosis of the event with the description (or a brief description of 
signs/symptoms/clinical course if the diagnosis is not available) and the date of 
onset and duration. 
•
Reason(s) for considering the event serious. 
•
Relationship of the event with the study drug or with the study procedure (eg, the 
causality according to the Investigator). 
•
Height, weight, or body surface area (where required for dose calculation). 
•
Underlying diagnosis and extent of disease. 
•
Lot number and expiration date of study drug (if available). 
•
Dose, route, frequency, and duration of study drug administered. 
•
Date of death (if applicable). 
•
Intervention(s) required. 
•
Concomitant therapy (including regimen[s] and indication). 
•
Pertinent laboratory data/diagnostic study (including dates). 
•
Pertinent medical history. 
•
Study drug status (dose interrupted, discontinued). 
•
Did event abate after interruption of study drug administration (if applicable)? 
•
Did event recur after study drug was reintroduced (if applicable)? 
In addition, the Investigator/Reporter must respond to any request for follow-up information 
or questions the Sponsor may have regarding the SAE within the same timelines as for the 
initial reports.  
12.7
Required Follow-up for All Adverse Events and Serious Adverse 
Events 
Appropriate consultation and follow-up evaluations should be carried out until the event has 
returned to baseline, has become chronic or stable per the Investigator.  
All SAEs must be promptly reported by the Investigator to their IRB/EC.  Should the FDA or 
other regulatory authorities require that the Sponsor submit additional data on the event, the 
Investigator will be asked to provide those data to the Sponsor in a timely fashion.  


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Note:  All subjects are to be followed for 30 days after last study drug administration in order to 
monitor for the occurrence of serious and non-serious AEs thought to be associated with 
study drug.  A longer period of time may be specified by the Sponsor if required to assure 
the safety of the subject.  Follow-up data concerning the SAE (eg, diagnostic test reports, 
physician's summaries, etc.) also must be submitted to the Sponsor, as they become 
available, preferably by telefax or e-mail transmission, until resolution of the SAE.  
12.8
Pregnancy Reporting 
All pregnancies in female subjects occurring from the date of Informed Consent signature 
until at least 30 days after the last study drug administration must be reported to the Sponsor’s 
Pharmacovigilance department.   
The Investigator must notify the Sponsor in an expedited manner (as per the same procedures 
and timelines described for expedited AE reporting in Section 12.5) by completing Part I of 
the Pregnancy Reporting and Outcome Form.   
Note:  Pregnancy itself is not an AE.  Only pregnancies considered related to study drug by the 
Investigator (ie, resulting from a drug interaction with a contraceptive medication) are 
considered as AEs and should be recorded on the AE eCRF.   
Investigators must actively follow-up, document and report to the Sponsor’s 
Pharmacovigilance department the outcome of all these pregnancies, even if the subject was 
withdrawn from the study.  Pregnancy outcomes are not recorded in the eCRF unless 
considered adverse events (eg, spontaneous abortion, congenital anomaly, etc.).   
Pregnancy outcomes must be reported to Sponsor’s Pharmacovigilance department by 
completing Part II of the same Pregnancy Reporting and Outcome Form used for the initial 
pregnancy notification.  Timelines vary according to the nature of the pregnancy outcome: 
•
For normal outcomes, the Sponsor should be notified within 45 days from 
birth/delivery.  
•
For abnormal outcomes, the fully completed form must be sent to Sponsor’s 
Pharmacovigilance department according to the same procedures and timelines 
described for expedited AE reporting in Section 12.5.    
Additional guidance can be found in the completion conventions provided by the Sponsor. 
13
PRECAUTIONS 
13.1
Precautions Regarding Procreation 
Men and women of childbearing potential will be informed as to the unknown risk to 
procreation while participating in this study and will be advised that they must use effective 
contraception during the study and follow-up period.  Sexually active pre-menopausal female 
subjects (and female partners of male subjects) must use adequate contraceptive measures, 
while on study and for at least 90 days after the last dose of study drug.  Sexually active male 
subjects must use adequate contraceptive measures, while on study and for at least 90 days 
after the last dose of study drug.  Effective birth control includes (a) IUD plus one barrier 
method, or (b) two barrier methods.  Effective barrier methods are male or female condoms, 
diaphragms, and spermicides (creams or gels that contain a chemical to kill sperm).  Oral, 
implantable, or injectable contraceptives may be affected by cytochrome P450 interactions, 
and are not considered effective for female subjects in this study. 


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A pregnancy test will be performed on each premenopausal female of childbearing potential 
prior to first study drug administration, and again at the end of the treatment and 30-Day 
Follow-up Visits.  A negative pregnancy test prior to administration of the study drug must be 
documented on the appropriate eCRF. 
If it is confirmed that a study participant has become pregnant while participating in this 
study, study drug administration will be discontinued immediately.  Any pregnancy occurring 
during this study will be reported immediately to the sponsor.  The investigator will then 
report follow-up information to the sponsor regarding the course of the pregnancy, including 
perinatal and neonatal outcome, regardless of the fact that the subject has discontinued 
participation in the study.  Once the newborn is determined to be healthy, as defined by and 
agreed upon by the sponsor and investigator, additional follow-up will no longer be required. 
13.1.1
Tivozanib 
Studies have not been performed to determine whether tivozanib affects reproductive function 
in males.  For this reason, men with partners of childbearing potential must take appropriate 
contraceptive measures while receiving tivozanib. 
It is not known whether tivozanib can cause fetal harm when administered to a pregnant 
woman or whether tivozanib can affect reproductive capacity.  There have been no studies in 
pregnant women.  Tivozanib should only be administered to women of childbearing capability 
when appropriate contraceptive measures have been taken and when pregnancy tests are 
negative. 
13.1.2
Sorafenib 
Sorafenib is classified as Pregnancy Category D.  Women of childbearing potential should be 
advised to avoid becoming pregnant while taking sorafenib.   
13.2
Additional Precautions 
Tivozanib 
Information regarding precautions and adverse events associated with tivozanib can be found 
in Section 3 (Introduction) and Section 13 (Precautions) of this protocol and in the 
Investigator’s Brochure.  Copies of both documents will be provided by the sponsor. 
Sorafenib 
Information regarding precautions and adverse events associated with sorafenib can be found 
in Appendix E, Sorafenib Prescribing Information. 
14
DATA EVALUATION AND STATISTICS 
14.1
General Design 
This is a Phase 3, randomized, controlled, open-label, parallel-arm, multi-national, 
multi-center study to compare tivozanib to sorafenib in subjects with refractory advanced 
RCC.  The primary endpoint is progression-free survival and the primary analysis is to 
compare the PFS of subjects treated with tivozanib to those treated with sorafenib. 


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14.2
Sample Size Justification 
A sample size of 322 subjects (161 subjects per treatment arm) with total number of 
255 events will provide 90% power to detect statistically significant differences between 
treatment arms with respect to progression-free survival as assessed by the independent 
radiology review.  Analysis of the primary endpoint will occur after 255 events have occurred.  
A simulation indicates that the analysis could be performed ≥ 6 months after the last subject is 
accrued.  The sample size was determined based on the following assumptions: 
•
The distribution of the PFS for the two treatment arms will be compared by using a 
Log-rank test with two-sided 5% significance level (α). 
•
The median PFS for subjects receiving sorafenib and tivozanib is 4 months and 
6 months, respectively (an increase of 2 months or 50%). 
•
An equal number of subjects will be assigned to each treatment arm. 
•
Enrollment will take 15 months. 
•
The drop out percentage per treatment arm will be 3%. 
The first secondary analysis will compare OS between the 2 treatment arms by using stratified 
Log-rank test, the stratification factors included in the primary analysis, and two-sided 0.8% 
significance level (utilizing a Lan-DeMets alpha spending function with an O’Brien-Fleming 
boundary).  The interim OS analysis will be done at the time of the final PFS analysis.  
Assuming a median OS for sorafenib of 12 months and a median OS for tivozanib of 
16 months, 245 OS events at the time of final OS analysis and 149 OS events at the time of 
final PFS analysis will yield approximately 61% power to demonstrate longer OS for 
tivozanib using the log-rank test, given 2.5% type I error (one-sided).  The final OS analysis 
will be performed when all subjects have been lost to follow-up, have withdrawn consent, or 
have died, or when all subjects in follow-up have been on-study for at least 2 years, whichever 
occurs first. 
The estimate was obtained by using East® statistical package Version 6.3 by Cytel Inc. 
14.3
Statistical Considerations 
All data collected in this study will be documented using summary tables and subject data 
listings.  Demographic, baseline characteristics, efficacy, and safety data will be summarized 
by treatment arm and the summary will be provided by visit (if applicable). 
Descriptive statistics will be provided for every variable.  The statistics will include sample 
size (n), mean, median, standard deviation (STD), minimum, and maximum for continuous 
variables.  Categorical variables will be summarized using number and percentages.  
14.3.1
Study Populations 
Three populations will be used in the analyses of the data: 
1. The intent-to-treat (ITT) population will consist of all randomized subjects; this 
population will be used for efficacy analysis, including primary endpoint 
(progression-free survival).  Subjects will be analyzed as randomized. 


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2. The per protocol (PP) population is defined as all randomized subjects who received at 
least two cycles (8 weeks) of protocol treatment (unless discontinued due to death or 
disease progression), have no major protocol deviations that will confound the effects 
of treatment, and meet all eligibility criteria.  Major protocol deviations include but are 
not limited to failure to satisfy eligibility criteria and taking prohibited medications 
during the treatment phase of the study.  Subjects will be analyzed as treated. 
3. The safety population (SAF) will include all subjects who received at least one dose of 
either study drug.  Subjects will be analyzed as treated. 
14.3.2
Subject Accountability, Demographics, and Baseline Characteristics 
All subjects enrolled (signed informed consent) in the study will be included in the summary 
of subject accountability by treatment arm and region.  The frequency and percentages of 
subjects who were enrolled in the study, discontinue from treatment before having 
documented disease progression, or discontinue from the study due to documented disease 
progression will be summarized for the ITT population.  
Descriptive statistics of subject demographics (age, gender, ethnicity, and race) and baseline 
characteristics will be summarized and presented by treatment arm.  
14.3.3
Protocol Deviations 
A subject will be classified as having a protocol deviation if one incurs an event belonging to 
any one of the following categories:  1) violation of the inclusion/exclusion criteria; 2) taking 
prohibited medications or treatments; 3) treatment misallocation; 4) violation of 
discontinuation criteria; 5) error in procedures and tests; and 6) missed visits.  Other deviation 
categories may be identified as appropriate. 
14.3.4
Efficacy 
The primary efficacy endpoint (PFS) and secondary efficacy endpoints (OS, ORR, and DoR) 
analyses will be carried out using the ITT population.  The primary efficacy endpoint of PFS 
also will be analyzed using the PP population. 
Analysis of the Primary Endpoint 
The primary analysis is to compare the PFS of subjects dosed with tivozanib with those 
subjects dosed with sorafenib.  The null hypothesis is that the median tivozanib PFS is equal 
to that of sorafenib and the alternative hypothesis is that the two PFS medians are not equal.  
The IRR will be the primary data source for the PFS analysis. 
The primary analysis will be carried out by using a stratified Log-Rank test, in which the 
stratification factors are IMDC risk category (favorable; intermediate; poor) and prior therapy 
(two prior VEGFR TKIs; a prior checkpoint inhibitor [PD-1 or PD1 L inhibitor] plus a prior 
VEGFR TKI; a prior VEGFR TKI plus any other systemic agent), and using a two-sided 
5% significance level.  The distribution of the PFS will be estimated using the Kaplan-Meier 
method.  The median event time and 2-sided 95% confidence interval for the median will be 
also provided.   


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Interim Analysis 
An interim analysis will be performed after 128 PFS events have been observed.  The interim 
analysis will look into the study’s futility using PFS as the efficacy evaluation endpoint.  This 
will utilize a Lan-DeMets error spending-type function with an O’Brien-Fleming stopping 
boundary with an estimated two-sided beta (Type II error) of 1.2 % spent during this interim 
look.   
The interim analysis will be performed by an independent statistician.  The independent 
statistician will evaluate and interpret the results of the interim analysis and will provide 
corresponding recommendation whether to stop the study for futility or for the study to 
continue until end of study condition has been met. 
Final analysis performed on PFS will be based on 255 events.  This could be performed 
≥ 6 months after the last subject is accrued.  PFS interim and final analyses will be carried out 
by using a stratified Log-Rank test with IMDC risk category and prior therapy as stratification 
factors. 
Handling of Missing Data 
For the purpose of PFS analyses, the following steps will be considered in case of missing 
data: 
a) Subjects with missing imaging at baseline will be considered non-evaluable for 
PFS estimation and will be excluded from the PFS analyses 
b) Subjects who have no tumor assessment after randomization will have PFS 
censored at the date of randomization, unless they died before the second 
scheduled tumor assessment. 
Further details and other cases will be described in the statistical analysis plan (SAP).   
Analysis of Secondary Endpoints 
The secondary endpoints (OS, ORR, and DoR) will be analyzed using the investigator and 
independent radiological review assessments.  The degree of agreement between the 
investigator and the independent assessment of responses will also be summarized and 
presented in a table.   
The first secondary analysis will compare the OS between the 2 treatment arms by using 
stratified Log-rank test and the stratification factors included in the primary analysis.  An 
interim OS analysis will be carried out at the time of the Final PFS analysis. 
Duration of response (DoR) will be analyzed using the same method as for the 
progression-free survival.   
The proportion of subjects achieving confirmed ORR (complete response [CR]+partial 
response [PR]) will be summarized and presented by treatment arms and cycle and will be 
compared between the two treatment arms using Cochran-Mantel-Haenszel (CMH) test with 
the same stratification factors used for the PFS analysis. 


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Exploratory Analyses
In order to evaluate if the timing of post-baseline radiological scan influenced the primary 
outcome, the time from randomization to post-radiological scan will be calculated and an 
exploratory analyses will be conducted.  Means and standard deviation of radiological scan 
time will be presented by treatment arms and cycle time.  Log-rank test will be used to test if 
cumulative percentages (survival curves) are equal (median time to each cycle from 
randomization) by treatment arms. 
Subgroup Analyses 
PFS subgroup analyses by gender, race, and age (< 65 years and ≥ 65 years) will be carried 
out using separate unadjusted Log-rank test for the ITT population. 
Definition of Efficacy Endpoints 
Progression-Free Survival (PFS) is defined as the time from randomization to first 
documentation of objective tumor progression (progressive disease [PD], radiological) 
according to RECIST (Version 1.1) or death due to any reasons whichever comes first. PFS 
data will be censored on the day following the date of last tumor assessment documenting 
absence of PD for subjects who do not have objective tumor progression and are still on study 
at the time of the analysis, are given anti-tumor treatment other than the study treatment, or 
are moved from treatment follow-up prior to documentation of objective tumor progression.  
Subjects having no tumor assessments after randomization who are not known to have died 
will have PFS censored on the date of randomization. 
Overall survival (OS) is defined as the time from the date of randomization to 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 on the date of randomization. 
Overall response rate (ORR) is defined as the proportion of subjects with confirmed CR or 
confirmed PR according to RECIST (Version 1.1), relative to the total population of 
randomized subjects.  Confirmed responses are those that persist on repeat imaging study at 
least 4 weeks after the initial documentation of response. 
Duration of response (DoR) is defined as the time from the first documentation of objective 
tumor response to the first documentation of objective tumor progression or to death due to 
any cause.  DoR data will be censored on the day following the date of the last tumor 
assessment documenting absence of PD for subjects who do not have tumor progression and 
are still on the study at the time of an analysis, are given antitumor treatment other than the 
study treatment, are removed from the study follow-up prior to documentation of objective 
tumor progression, died of non-cancer related cause, including death due to unknown cause in 
the absence of documented disease progression.  DoR will only be calculated for the 
subgroup of subjects with an objective tumor response (PR or CR). 
14.3.5
Safety Data 
The safety parameters (study drug exposure, adverse events, laboratory parameters, vital 
signs, medical history, concomitant medications, and physical examinations) will be analyzed 
using the SAF population. 


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Adverse Events 
Adverse events will be coded by system organ class (SOC) and preferred term using the 
Medical Dictionary for Regulatory Activities (MedDRA™) Dictionary (Version 18.0 or later).  
Summary tables will be presented for treatment emergent adverse events by treatment arm.  
An overall presentation of treatment emergent adverse event information will show the 
number and percent of subjects with at least one event by treatment arm.  
Adverse event information will be also presented by NCI CTCAE severity grade and 
relationship to study treatment.  If a subject had more than one occurrences of an adverse 
event, the most severe grade or most highly treatment-related category will be used in the 
summary tables.  
All adverse events will be listed.  The following listings will be also provided:  1) subjects 
who died during the study; 2) subjects with treatment emergent SAEs; 3) subjects who 
discontinued due to treatment emergent AEs; and 4) other significant treatment emergent 
adverse events. 
Laboratory Analyses 
Laboratory assessments (hematology, serum chemistry, urinalysis, and coagulation 
parameters) will be summarized descriptively by treatment arm and visit.  The change from 
baseline will be summarized for all post-baseline evaluations. 
The shift (based on normal ranges) from baseline will be summarized by treatment arm and 
visit.  The significant of shifts in laboratory parameters may be evaluated within each 
treatment arm using generalized McNemar’s test. 
The signed-rank test may be used to evaluate the within-group mean change from baseline.  
The mean change from baseline between the treatment arms will be compared using a 
Rank-Sum test. 
The first laboratory observation will be taken when the lab tests are repeated.  However, if the 
first observation is missing, then the repeat value within the same visit will be used. 
All laboratory values will be listed by panel.  Out-of-reference range values will be flagged 
(L/H) and presented in a listing.   
Physical Examination, Vital Signs, and Other Safety Parameters 
Vital signs and ECG results will be summarized descriptively and presented by visit and 
treatment arm.  The change from baseline in vital signs will be summarized for all 
post-baseline evaluations.  The signed-rank test may be used to evaluate within-group mean 
change from baseline.  
The shift from baseline in physical examination will also be presented by visit with subjects 
classified as having any shift from normal to abnormal, from abnormal to normal, or no 
change.  
ECOG performance status will be summarized descriptively and presented by visit and 
treatment arm. 
Vital signs, physical examination, ECG results, and ECOG performance status will be listed 
for all treated subjects.   


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Concomitant Medication 
For each concomitant medication taken during the study, the generic component will be 
identified using the World Health Organization Drug Dictionary (WHO-DD; WHODDB3 
ENHANCED JUN 2015).  Frequencies and percentages of the subjects taking each 
concomitant medication will be tabulated by preferred medication term and treatment arm.  
A subject will only be counted once within each generic component term. 
14.3.6
Safety Monitoring Committee 
A safety monitoring committee (SMC) will monitor the safety data from this study on a 
periodic basis in order to identify any issues and risks, as well as provide recommendations 
regarding the study design and conduct.  The SMC is composed of six members, all of whom 
are qualified clinicians in general oncology and renal cell carcinoma and have practical 
experience conducting and monitoring the safety and efficacy of clinical trials. 
The first review of the cumulative safety data will occur after 50 subjects have been 
randomized to each treatment arm and approximately every 6 months thereafter. The 
frequency may be modified at the discretion of the SMC. 
Full details are described in the SMC charter. 
14.3.7
Pharmacokinetic Parameters 
Tivozanib concentration will be summarized descriptively and presented by visit.   
14.3.8
Imaging Process 
Two primary radiologists will independently review the images for each subject at each time 
point and if the results are discordant, then a third radiologist, blinded to treatment, will 
perform an adjudication of the radiology results.  Additionally, an independent radiologist will 
verify the presence of measurable disease according to RECIST Version 1.1 guidelines, at the 
time of screening until progressive disease. 
The imaging processes will be fully described in the radiographic charter. 
15
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
15.1
Study Monitoring 
The sponsor has responsibility to governing regulatory authorities to take all reasonable steps 
to ensure the proper conduct of the study with respect to study ethics, protocol adherence, and 
data integrity and validity. 
This study will be closely monitored by representatives of the sponsor (and/or designee) 
throughout its duration.  Monitoring will be in the form of personal visits with the investigator 
and their staff as well as any appropriate communications by telephone, telefax, mail, or 
e-mail transmission.  The purpose of these contacts is to review study progress, investigator, 
and subject adherence to protocol requirements and any emergent problems associated with 
the conduct of the study.  The following points will be usually assessed during monitoring 
visits at the site: 
•
Required regulatory documentation 
•
Signed informed consent documents 


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•
Subject accrual and follow up 
•
Study drug inventory records 
•
Investigator and subject compliance to the study protocol 
•
Concomitant therapy use 
•
Adverse event documentation 
•
Data as accurate, complete, and verifiable when compared to source documents. 
The investigator and study staff are expected to cooperate with monitors during such visits 
and provide them with all relevant study documents. 
15.2
Audits and Inspections 
The study may be evaluated by AVEO auditors (and/or designees) and government inspectors 
who must be allowed access to eCRFs, source documents, and other study files.  AVEO 
reports will be kept confidential.  The investigator should promptly notify AVEO of any 
audits scheduled by any regulatory authorities, and promptly forward copies of audit reports. 
16
QUALITY CONTROL AND QUALITY ASSURANCE 
The sponsor performs quality control and assurance checks on all clinical studies that it 
sponsors.  Before enrolling any subjects in this study, sponsor personnel and the investigator 
review the protocol, Investigator’s Brochure, eCRFs and instructions for their completion, 
procedure for obtaining informed consent, and procedure for reporting AEs and SAEs.  
A qualified representative of the sponsor monitors the conduct of the study by visiting the site 
and by contacting the site by telephone and e-mail.  During these site visits, information 
recorded in the eCRFs is verified against source documents/hospital records.   
17
ETHICS 
17.1
Ethical Conduct of the Study/Conditions of Testing 
In sponsoring this study, it is the intention of AVEO Pharmaceuticals, Inc. to obtain subject 
safety data for submission to regulatory authorities.  In agreeing to conduct this investigation, 
the investigative facility agrees to follow all requirements stipulated in this protocol as well as 
regulations described in the US Code of Federal Regulations (CFR), the European 
Commission Directive 2001/20/EC, Directive 2005/28/EC, or by the National Regulatory 
Authorities concerning: 
•
General Responsibilities of Investigators (Title 21CFR, Part 312) 
•
Protection of Human Subjects (Title 21 CFR, Part 50) 
•
Institutional Review Boards (Title 21 CFR, Part 56). 
In addition, the investigator agrees to perform the study in accordance with ICH guidelines for 
GCP and/or the Declaration of Helsinki. 


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17.2 
Institutional Review / Ethics Committee 
The investigator will submit this protocol, any protocol modifications, and the subject consent 
form to be utilized in this study, to the appropriate IRB or EC for review and approval.  This 
committee must operate in accordance with the US Code of Federal Regulations, Title 21 
CFR Part 56 or ICH GCP or European regulations.  A letter confirming approval of the 
protocol, and the informed consent document, must be forwarded to the sponsor prior to 
initiation of this study.  The investigator will not start the study, nor will study drug be 
shipped to the investigational site, before providing the sponsor with evidence of this 
approval.  
The investigator is responsible for assuring continuing review and approval of the clinical 
study.  The investigator must also promptly report all changes in the research activity and all 
unanticipated problems involving risk to the subjects or others to their IRB or EC.  The 
investigator will not make any changes in the protocol without IRB or EC approval, except 
when necessary to eliminate apparent immediate hazards to the subjects.  The investigator will 
provide progress reports to the IRB or EC as required by the IRB or EC.  If the study remains 
in progress for more than 1 year, the investigator must obtain annual renewal and re-approval 
from the IRB or EC where appropriate.  Documentation of renewal must be submitted to the 
sponsor.  The investigator will provide notice to the IRB or EC of completion of participation 
in the study. 
17.3
Written Informed Consent 
The investigator agrees to protect the rights, safety, and welfare of the subjects entered into 
the study, including obtaining informed consent prior to performing any study-related 
procedures and informing each subject that the study drugs are being used for investigational 
purposes.  A copy of all IRB- or EC-approved consent form document to be utilized during 
this study must be submitted to the sponsor or designee for review. 
Prior to entry into this study, the purpose and nature of the study and possible adverse effects 
must be explained to each subject.  All questions about the study should be answered to the 
satisfaction of the subject or the subject’s legal representative.  It is the responsibility of the 
investigator to obtain written informed consent from each subject, thereby attesting that 
consent was freely given.  An investigator listed on the Form FDA 1572 will then co-sign the 
informed consent document.  This consent must be obtained in accordance with the US Code 
of Federal Regulations, Title 21 CFR Part 50 or in accordance with the ICH GCP.  A copy of 
the signed and dated informed consent document should then be given to the subject.  The 
original executed version must remain in the subject’s file and must be available for 
verification by a representative of the sponsor (or designee). 
17.4
Conditions for Modifying or Terminating the Study 
17.4.1
Modification of the Study Protocol 
In the event that modifications in the experimental design, dosages, parameters, subject 
selection, etc., of the protocol are indicated or required, such changes will only be instituted 
following consultation between the sponsor and investigator and will be accomplished 
through formal amendment(s) to this protocol and approval by the appropriate review 
committees, except when necessary to immediately eliminate apparent hazards to subjects. 


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A modification to the protocol will not be made without the express written approval of the 
sponsor.  Any amendment prepared by the sponsor will be implemented according to the 
sponsor’s standard operation procedures and will be reported to the appropriate regulatory 
body, the appropriate IRB(s) or EC(s), and made a formal component of the protocol 
document. 
17.4.2
Modification of the Informed Consent Document 
In the event that modifications in the experimental design, dosages, parameters, subject 
selection, etc., of the protocol are indicated or required, and in the event that such 
modifications substantially alter the study design or increase the potential risk to subjects, the 
investigator will prepare a revision to the existing informed consent document.  Such a 
revision will be reviewed and approved by the appropriate IRB(s) or EC(s), and 
documentation of this approval will be forwarded to the sponsor for submission to the 
appropriate regulatory body.  
In addition, all current study participants, as well as subsequent study candidates, will be 
informed of the study design modification or increase in potential risk, and written informed 
consent for the modification/risk will be obtained as outlined above (see Section 18.3, Written 
Informed Consent). 
17.4.3
Termination of the Study 
Should the sponsor and/or the investigator(s) discover conditions, during the course of the 
study, that indicate that it should be discontinued, an appropriate procedure for termination 
will be instituted. 
17.4.4
Deviation From the Protocol 
The study is to be conducted as described in this protocol.  Under no circumstances should the 
protocol be modified for any subject.  If a protocol deviation should occur it is to be 
documented on the protocol deviation log and reported to the IRB/EC per their guidelines. 
17.5
Documents to be Submitted to the Sponsor 
The following documents must be submitted to the sponsor or delegate prior to study drug 
shipment: 
1. Signed and dated FDA Form 1572 or the equivalent.  
Note:  In conducting this study, the investigator agrees to comply with commitments listed under 
Section 9 of Form 1572. 
2. Signed and dated curriculum vitae (CV) of the principal investigator and each 
sub-investigator named on the FDA Form 1572.  Physician CVs should be current 
(updated within 2 years) and should include medical license numbers if available or 
where applicable.   
Note:  A sub-investigator is defined as a clinician responsible for study-related medical decisions, 
diagnoses, and treatment. 
1. Written, signed notification of IRB or EC approval of the study protocol. 
2. Written, signed notification of the approval of the informed consent document to be used 
during the study. 


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3. The IRB- or EC-approved informed consent document to be used during the study.   
4. A list of IRB committee members or certification that there is no conflict of interest. 
5. Laboratory normal ranges for the local laboratories to be utilized if applicable.  Name, 
location, certification number, and date of certification of all laboratories utilized must 
also be provided, where available and applicable. 
6. Signed and dated Protocol Signature Page. 
7. Fully executed Clinical Trial Agreement. 
8. Signed and dated Financial disclosure forms for the principal investigator and each 
sub-investigator named on the FDA Form 1572.   
18
INVESTIGATOR RESPONSIBILITIES 
18.1
Medical Supervision 
An investigator conducting a clinical study with an investigational agent is required to comply 
with regulations described in US Code of Federal Regulations, Title 21 CFR Part 312, the 
European Commission Directive 2001/20/EC, Directive 2005/28/EC, and ICH GCP as well as 
local laws and regulations. 
Medical supervision for the conduct of this protocol is the responsibility of the principal 
investigator.  The principal investigator must name all sub-investigators and may delegate 
certain day-to-day activities to such sub-investigators, but, retains overall responsibility for 
ensuring that the study is conducted properly and in accordance with the design and intent 
herein.  A memorandum outlining the specifics of the delegation will be maintained at the 
investigational site, in the study files, and will be updated as appropriate.  The principal 
investigator is responsible for ensuring that drugs and devices are available for treating 
possible medical emergencies.  The principal investigator is required to ensure compliance 
with respect to the investigational drug schedule, visit schedule, and procedures required by 
the protocol.  The principal investigator is responsible for ensuring that the study is conducted 
according to sound medical practices. 
18.2
Confidentiality 
All goods, materials, information (oral or written) and unpublished documentation provided to 
the investigator (or any company acting on their behalf), inclusive of this protocol, the subject 
case report forms, and the Investigator's Brochure are the exclusive property of the sponsor.  
Documents and information provided to the investigator by the sponsor may not be given or 
disclosed by the investigator or by any person within his authority in part or in totality to any 
unauthorized person without the prior written formal consent of the sponsor.  
It is specified that the submission of this protocol and other necessary documentation to the 
IRB or EC is expressly permitted, the IRB or EC members having the same obligation of 
confidentiality. 
The investigator shall consider as confidential and shall take all necessary measures to ensure 
that there is no breach of confidentiality in respect of all information accumulated, acquired or 
deduced in the course of the study, other than that information to be disclosed to a third party 
mandated by applicable law. 


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Note:  Any language relating to these issues appearing in the Clinical Trial Agreement will supersede that 
which is outlined in this section. 
18.3
Use of Information and Publication 
The investigator, the institution, and its personnel understand and agree that participation in a 
multi-center study involves a commitment to publish the data from the study in a cooperative 
publication prior to publication or oral presentation of study results on an individual basis.  
Upon completion of the study and evaluation by sponsor of all data from the study, or upon 
early termination or abandonment of the study pursuant to the terms herein, the institution and 
investigator may publish or disclose the results of the study, subject to the following: 
1. Review Period.  A copy of such proposed publication will be given to the sponsor for 
review at least sixty (60) days prior to the date of submission for publication or of 
public disclosure.  The sponsor will complete its review within this review period and 
will have authority to require that the institution and/or the investigator delete any 
reference to confidential information (other than the results) from the disclosure.   
2. Patent Filings.  If during the review period, the sponsor notifies the institution that it 
desires patent applications to be filed on any sponsor’s inventions (defined below) 
disclosed or contained in the disclosures, the institution and the investigator will defer 
publication or other disclosure for a period, not to exceed an additional sixty (60) days, 
sufficient to permit the sponsor or its designee to have filed or to file any desired 
patent applications.   
Multi-Center Studies.  No submission for publication or public disclosure by the institution or 
the investigator will be made until results from all centers have been received and analyzed by 
the sponsor, or the multi-center study has been terminated or abandoned at all centers.  If a 
publications committee, or a committee of investigators, is formed for publication of results of 
the multi-center clinical study, any separate publication by the institution or the investigator 
will be delayed until the initial publication by the committee or a determination is made by the 
committee not to make such publication.  If the committee does not produce an initial draft of 
a manuscript or abstract of results from all centers within eighteen (18) months of completion 
of the study at all centers and the committee has not notified the institution or investigator that 
it intends to produce a manuscript or abstract in a timeframe satisfactory to the institution and 
investigator, then the institution and investigator may publish or otherwise disclose the results 
for non-commercial purposes, subject to the terms mentioned in Paragraphs 1 and 2 
immediately above. 
Note:  Any language relating to these issues appearing in the Clinical Trial Agreement will supersede that 
which is outlined in this section. 
18.4
Drug Dispensing Inventory 
Study center personnel will maintain adequate records of the receipt, dispensation, and 
disposition of all study drugs that the sponsor ships to the site.  Records will be maintained, 
either on a form to be provided by the sponsor or on a reasonable facsimile authorized for use 
by the sponsor, and should include appropriate dates, quantities received, quantities dispensed, 
and the identification code of the subject who received the study drug. 


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The investigator agrees to administer study drug only to subjects under their personal 
supervision.  The investigator will not supply study drug to any person not authorized to 
receive it. 
18.5
Handling and Disposal of Investigational Materials 
Study drug should be stored in a secure location, under the indicated conditions (see 
Appendix F; Tivozanib Study Drug Information and Appendix E, Sorafenib Prescribing 
Information).  After study drug is prepared for delivery and administered, the health care 
professional will maintain an inventory of all used bottles of study drug, after which all such 
supplies may be destroyed in an appropriate manner according to institutional policy.  
Destruction of such supplies will be documented.  Information regarding the number of 
bottles utilized for each subject, as well as the dose of study drug administered to the subject, 
will be recorded on the appropriate drug inventory form. 
Periodically throughout and at the conclusion of the study, unused bottles of study drug will 
be inventoried by a representative of the sponsor (or designee).  At the completion of this 
study, all unused study materials will be destroyed by the site or returned to the sponsor (or 
designee).  Destruction of study drug by the site can only occur after the sponsor (or designee) 
has collected the site’s SOP for drug destruction.  
18.6
Recording and Processing of Data 
Clinical study data for this study will be captured in an electronic format.  Electronic data 
capture (EDC) services will be provided by the contract research organization (CRO).  The 
investigator agrees to provide all information requested on the eCRF in an accurate manner 
according to instructions provided.  Electronic CRFs are designed for computer processing 
and analysis.  All data must be carefully entered to permit meaningful interpretation.  
Corrections to entered data will be tracked within the EDC system.  Data must be entered onto 
eCRFs in a timely fashion. 
An eCRF is required to be submitted for every subject who is randomized.  This includes 
submission of retrievable data on subjects who withdraw before completion of the study.  
Prior to submission, eCRFs must be reviewed for completeness and accuracy, and signed and 
dated where indicated, by either the principal investigator or a physician sub-investigator 
whose name is listed on the Form FDA 1572 for this study.
All data from the study will be exported to the sponsor, AVEO Pharmaceuticals, Inc. 
(Cambridge, Massachusetts, USA). 
18.7
Source Document Requirements 
The investigator will maintain adequate and accurate records for each subject who is 
randomized.  Source documents such as hospital, clinic, or office charts; laboratory reports; 
study worksheets; and signed informed consent documents are to be included in the 
investigator’s files along with subject study records. 
The sponsor (or designee) will check eCRF entries against source documents according to the 
guidelines of GCP.  The consent form will include a statement by which subjects allow the 
sponsor (or designee), as well as authorized regulatory agencies, to have direct access to 
source data that support data on the eCRF (eg, subject medical files, appointment books, 


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original laboratory records, etc.).  The sponsor (or designee), bound by secrecy, will not 
disclose subject identities or personal medical information. 
18.8
Laboratory Reports 
Local laboratories will be used for laboratory safety evaluations this study.  Laboratory safety 
evaluations must be performed at the intervals specified.  If unexplained laboratory 
abnormalities occur, corroborative tests will be performed until the laboratory parameter has 
returned to normal and/or adequate explanation of the abnormality has been provided. 
Copies of any additional records pertinent to the study (eg, laboratory data, radiological 
reports, subject chart summaries, autopsy reports) must be made available to the sponsor or 
regulatory authorities, if requested, with due precaution taken to ensure subject 
confidentiality. 
18.9
Subject Confidentiality 
Every effort will be made to maintain the anonymity and confidentiality of subjects during 
this clinical study.  Coded subject identifiers will be utilized at all times (including in any 
publications) when referring to a particular subject.  However, because of the experimental 
nature of this treatment, at mutually agreeable times, the institution and investigator will give 
the sponsor and its designees and governing regulatory agencies (as provided by applicable 
law) access to all records, documentation (however stored) relating to the study or to the care 
of study subjects, for sponsor or designees to monitor the study for source documentation 
verification, and/or for audit purposes, and for the sponsor or designee, to inspect the facilities 
to verify compliance with this protocol and the clinical study agreement.  Subjects’ medical 
records will be made available where appropriate for the purpose of source documentation 
verification procedures. 
19
DATA HANDLING AND RECORDKEEPING 
19.1
Inspection of Records 
The investigator agrees that qualified representatives of the sponsor and regulatory agencies 
will have the right, during and after the study, to conduct inspections and to audit and review 
medical records pertinent to the clinical study as permitted by the regulations.  Subject 
confidentiality will be maintained unless disclosure is required by regulations. 
At mutually agreeable times, the institution and investigator will give the sponsor and its 
designees and governing regulatory agencies (as provided by applicable law) access all 
records, documentation (however stored) relating to the study or to the care of study subjects, 
for sponsor or designees to monitor the study, for source document verification, and/or for 
audit purposes, and for sponsor or designee to inspect the facilities to verify compliance with 
this protocol and the clinical study agreement.  Subjects’ medical records will be made 
available where appropriate for the purpose of source document verification procedures. 
19.2
Retention of Records 
The investigator will maintain records for this study, which includes subject’s eCRFs, medical 
records, laboratory reports, signed informed consent forms, safety reports, plus all other 
pertinent data.  The investigator will retain study medication disposition records, copies of 
eCRFs (or electronic files), and source documents for the maximum period required by the 


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country in which the study will be conducted, or the period specified by the sponsor, 
whichever is longer. 
United States federal law requires that the investigator retain copies of all files pertaining to 
the study (ie, records of study article disposition, signed informed consent documents, case 
report forms, all correspondence, dates of monitoring visits, and records which support them) 
for a period of 2 years following the date of marketing application approval of the drug, in the 
indication being investigated in the study and until there are no pending or contemplated 
marketing application, or 2 years following the sponsor’s formally discontinuing worldwide 
clinical development of the study drug, as notified by the sponsor, whichever is longer.  
European Commission Directive 2005/28/EC requires that investigators and sponsors shall 
retain the essential documents for at least 5 years after completion of a clinical study. 
If the investigator relocates, retires, or withdraws for any reason from the study, study records 
may be transferred to an acceptable designee, such as another investigator within the 
institution.  Prior notice of such transfer will be provided in writing to the sponsor.  The 
investigator must obtain written permission from the sponsor prior to disposing of any 
records.  
20
REFERENCES 
1  Nakamura K, Taguchi E, Miura T, et al. KRN951, a highly potent inhibitor of vascular 
endothelial growth factor receptor tyrosine kinases, has antitumor activities and affects 
functional vascular properties. Cancer Research. 2006;66:9134-9142. 
2  Holash J, Davis S, Papadopoulos N, et al. VEGF-Trap: a VEGF blocker with potent 
antitumor effects (abstract). Proc Natl Acad Sci USA. 2002;99(17):11393-11398. 
3  Ferrara N and Alitalo K. Clinical applications of angiogenic growth factors and their 
inhibitors. Nat Med. 1999;5(12):1359-1364. 
4  Folkman J. Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat Med.
1995;1(1):27 - 31. 


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5 
Liekens S, de Clercq E, and Neyts J. Angiogenesis: Regulators and clinical applications. 
Biochem Pharmacol. 2001;61:253-270. 
6  Neufeld G, Cohen T, Gengrinovitch S, and Poltorak, Z. Vascular endothelial growth factor 
(VEGF) and its receptors. FASEB J. 1999;13:9-22. 
7  van der Veldt AAM, Boven E, Helgason HH, et al. Predictive factors for severe toxicity of 
sunitinib in unselected patients with advanced renal cell cancer.  British Journal of Cancer. 
2008;99, 259 – 265. 


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21
APPENDICES 


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APPENDIX A 
RESPONSE EVALUATION CRITERIA IN SOLID TUMORS 
(RECIST) VERSION 1.1 
Response criteria were adapted from:  Response Evaluation Criteria in Solid Tumors (RECIST) 
Criteria; Version 1.1, 2009 (http://www.eortc.be/Recist/documents/RECISTGuidelines.pdf). 
1.1
Assessment of Overall Tumor Burden and Measurable Disease 
To assess objective response, it is necessary to estimate the overall tumor burden at baseline and 
use this as a comparator for subsequent measurements.  Only subjects with measurable disease at 
baseline should be included in protocols where objective tumor response is an endpoint.  
Measurable disease is defined by the presence of at least one measurable lesion.  
A measurable lesion is defined as one that can be accurately measured in at least one dimension 
(longest diameter in the plane of measurement is to be recorded) with a minimum size of: 
•
10mm by CT scan (CT scan slice thickness no greater than 5 mm). 
•
10mm caliper measurement by clinical exam (lesions which cannot be accurately 
measured with calipers should be recorded as non-measurable). 
•
20mm by chest X-ray. 
Non-measurable lesions are defined as all other lesions, including small lesions (longest diameter 
<10mm or pathological lymph nodes with ≥10 to <15mm short axis) as well as truly 
non-measurable lesions.  Lesions considered truly non-measurable include:  leptomeningeal 
disease, ascites, pleural or pericardial effusion, inflammatory breast disease, lymphangitic 
involvement of skin or lung, abdominal masses/abdominal organomegaly identified by physical 
exam that is not measurable by reproducible imaging techniques. 
Special considerations regarding lesion measurability: 
Bone lesions: 
Bone scan, PET scan or plain films are not considered adequate imaging techniques to measure 
bone lesions.  However, these techniques can be used to confirm the presence or disappearance 
of bone lesions.  Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue 
components, that can be evaluated by cross sectional imaging techniques such as CT or MRI can 
be considered as measurable lesions if the soft tissue component meets the definition of 
measurability described above.  Blastic bone lesions are non-measurable.  
Cystic lesions: 
Lesions that meet the criteria for radiographically defined simple cysts should not be considered 
as malignant lesions (neither measurable nor non-measurable) since they are, by definition, 
simple cysts.  ‘Cystic lesions’ thought to represent cystic metastases can be considered as 
measurable lesions, if they meet the definition of measurability described above.  However, if 


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noncystic lesions are present in the same subject, these are preferred for selection as target 
lesions.   
Lesions with prior local treatment: 
Tumour lesions situated in a previously irradiated area, or in an area subjected to other 
loco-regional therapy, are usually not considered measurable unless there has been demonstrated 
progression in the lesion.   
1.2 
Baseline Documentation of Target and Non-Target Lesions 
Baseline documentation of tumor sites may include imaging assessment of disease in the chest, 
abdomen, and pelvis.  A baseline imaging study of the brain is also required.  All baseline tumor 
measurements must be documented within 4 weeks prior to start of therapy.  
1.2.1 Target Lesions 
All measurable lesions up to a maximum of five lesions total (and a maximum of two lesions per 
organ) representative of all involved organs should be identified as target lesions and will be 
recorded and measured at baseline (this means in instances where patients have only one or two 
organ sites involved a maximum of two and four lesions respectively will be recorded).  Target 
lesions should be selected on the basis of their size (lesions with the longest diameter), be 
representative of all involved organs, but in addition should be those that lend themselves to 
reproducible repeated measurements.  It may be the case that, on occasion, the largest lesion does 
not lend itself to reproducible measurement in which circumstance the next largest lesion which 
can be measured reproducibly should be selected.  A sum of the diameters (longest for non-nodal 
lesions, short axis for nodal lesions) for all target lesions will be calculated and reported as the 
baseline sum diameters.  If lymph nodes are to be included in the sum, then as noted above, only 
the short axis is added into the sum.  The baseline sum diameters will be used as reference to 
further characterise any objective tumour regression in the measurable dimension of the disease.  
1.2.2 Non-Target Lesions 
All other lesions (or sites of disease) including pathological lymph nodes should be identified as 
non-target lesions and should also be recorded at baseline.  Measurements are not required and 
these lesions should be followed as ‘present’, ‘absent’, or in rare cases ‘unequivocal 
progression’.  In addition, it is possible to record multiple non-target lesions involving the same 
organ as a single item on the case record form (eg ‘multiple enlarged pelvic lymph nodes’ or 
‘multiple liver metastases’).  
1.3 
Tumor Response Criteria
1.3.1 Evaluation of Target Lesions 


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Complete Response (CR): 
Disappearance of all target lesions.  Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to 
<10 mm.  
Partial Response (PR): 
At least a 30% decrease in the sum of diameters of target lesions, 
taking as reference the baseline sum diameters.  
Progressive Disease (PD): 
At least a 20% increase in the sum of diameters of target lesions, 
taking as reference the smallest sum on study (this includes the
baseline sum if that is the smallest on study).  In addition to the
relative increase of 20%, the sum must also demonstrate an absolute 
increase of at least 5 mm.  (Note:  the appearance of one or more 
new lesions is also considered progression). 
Stable Disease (SD): 
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum
diameters while on study.  
1.3.2 Evaluation of Non-Target Lesions 
Complete Response (CR): 
Disappearance of all non-target lesions and normalisation of tumour 
marker level.  All lymph nodes must be non-pathological in size 
(<10mm short axis).  
Non-CR/Non-PD: 
Persistence of one or more non-target lesion(s) and/or maintenance 
of tumour marker level above the normal limits.  
Progressive Disease (PD): 
 Unequivocal progression of existing non-target lesions.  (Note: 
the appearance of one or more new lesions is also considered
progression). 
1.4 
Evaluation of Best Overall Response
The best overall response is the best response recorded from the start of the study treatment until
the end of treatment taking into account any requirement for confirmation.  The patient’s best
overall response assignment will depend on the findings of both target and non-target disease and
will also take into consideration the appearance of new lesions.  In non-randomized trials where
response is the primary endpoint, confirmation of PR or CR is needed to deem either one the ‘best 
overall response’.  


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CR = complete response, PR = partial response, SD = stable disease,  
PD = progressive disease, and NE = inevaluable 
Note:   
Subjects with a global deterioration of health status, requiring discontinuation of treatment without 
objective evidence of disease progression at that time, should be reported as “symptomatic 
deterioration.  ” Every effort should be made to document the objective progression, even after 
discontinuation of treatment. 
Conditions that may define “early progression, early death, and inevaluability” are study-specific and 
should be clearly defined in each protocol (depending on treatment duration, treatment periodicity). 
In some circumstances it may be difficult to distinguish residual disease from normal tissue. When the 
evaluation of complete response depends upon this determination, it is recommended that the residual 
lesion be investigated (fine needle aspiration/biopsy), before confirming the complete response status. 
1.5 
Guidelines for Evaluation of Measurable Disease 
All measurements should be recorded in metric notation using a ruler or calipers.  All baseline 
evaluations should be performed as close as possible to the treatment start and never more than 
4 weeks before the beginning of treatment.  
Note:  Tumor lesions in a previously irradiated area are not optimally considered measurable 
disease.  If the investigator thinks it appropriate to include them, the conditions under which such 
lesions should be considered must be defined in the protocol.  
The same method of assessment and the same technique should be used to characterise each 
identified and reported lesion at baseline and during follow-up.  Imaging based evaluation should 
always be done rather than clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam.  
DETERMINATION OF TUMOR RESPONSE
Target Lesions
Non-Target Lesions
New Lesions
Response 
Assessment
CR
CR
No
CR
CR
Non-CR/Non-PD
No
PR
CR
Not Evaluated
No
PR
PR
Non-PD or Not All
Evaluated
No
PR
SD
Non-PD or Not All 
Evaluated
No
SD
Not All Evaluated
Non-PD
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD


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Clinical lesions will only be considered measurable when they are superficial and P10mm 
diameter as assessed using calipers (eg skin nodules).  For the case of skin lesions, 
documentation by colour photography including a ruler to estimate the size of the lesion is 
suggested.  
For Chest lesions, Chest CT is preferred over chest X-ray, particularly when progression is an 
important endpoint, since CT is more sensitive than X-ray, particularly in identifying new 
lesions.  However, lesions on chest X-ray may be considered measurable if they are clearly 
defined and surrounded by aerated lung.  
Cross Sectional Imaging:  CT is the best currently available and reproducible method to 
measure lesions selected for response assessment.  This guideline has defined measurability of 
lesions on CT scan based on the assumption that CT slice thickness is 5mm or less.  When CT 
scans have slice thickness greater than 5 mm, the minimum size for a measurable lesion should 
be twice the slice thickness.  MRI is also acceptable in certain situations (eg for body scans). 
Ultrasound is not useful in assessment of lesion size and should not be used as a method of 
measurement.  If new lesions are identified by ultrasound in the course of the study, confirmation 
by CT or MRI is advised.  If there is concern about radiation exposure at CT, MRI may be used 
instead of CT in selected instances.  
1.6 
Duration of Response 
1.6.1 Duration of Response 
The duration of overall response is measured from the time measurement criteria are first met for 
CR/PR (whichever is first recorded) until the first date that recurrent or progressive disease is 
objectively documented (taking as reference for progressive disease the smallest measurements 
recorded on study).  The duration of overall complete response is measured from the time 
measurement criteria are first met for CR until the first date that recurrent disease is objectively 
documented.  
1.6.2 Duration of Stable Disease 
Stable disease is measured from the start of the treatment until the criteria for progression are 
met, taking as reference the smallest sum on study (if the baseline sum is the smallest, this is the 
reference for calculation of PD).  
1.6.3 Time to Disease Progression 
Defined as the time from the date of first day of enrollment to progression as assessed by the 
conventional response criteria, death, or the start of further antitumor therapy.  Subjects lost to 
follow-up will be censored at their last known alive date. 


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APPENDIX B 
ECOG PERFORMANCE STATUS EVALUATION 
Grade 
Eastern Cooperative Oncology Group (ECOG)* 
0 
Fully active, able to carry on all pre-disease performance without restriction. 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light house work, office work. 
2 
Ambulatory and capable of all selfcare but unable to carry out any work 
activities.  Up and about more than 50% of waking hours. 
3 
Capable of only limited selfcare, confined to bed or chair more than 50% of 
waking hours. 
4 
Completely disabled.  Cannot carry on any selfcare.  Totally confined to bed or 
chair. 
5 
Death 
*Oken M, Creech RH, Tormey DC, Horton J, Davis TE, McFadden E, Carbone PP. Toxicity and response criteria of the eastern cooperative 
oncology group.  Am J Clin Oncol. (CCT) 1982; 5:649-655. 


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APPENDIX C 
CYTOCHROME P450 (CYP3A4) INHIBITORS AND INDUCERS 
Cytochrome P450 (CYP3A4) Drug interaction table 
STRONG* INHIBITORS 
STRONG* INDUCERS 
Ketoconazole  
Rifabutin  
Nefazodone 
Rifampin  
Nelfinavir 
Ritonavir 
* Strong inhibition implies that it can cause a > 5-fold increase in the plasma AUC values or > 80% decrease in 
clearance of sensitive CYP substrates. 


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APPENDIX D 
RECOMMENDED ANTI-HYPERTENSIVE MEDICATIONS 
Agent 
Initial Dose 
Intermediate Dose 
Maximum Dose 
Dihydropyridine (DHP) Calcium Channel Blockers 
Nifedipine XL 
30 mg po qd 
60 mg po qd 
90 mg po qd 
Amlodipine 
2.5 mg po qd 
5 mg po qd 
10 mg po qd 
Felodipine 
2.5 mg po qd 
5 mg po qd 
10 mg po qd 
Angiotensin Converting Enzyme (ACE) Inhibitors
Captopril 
12.5 mg po tid 
25 mg po tid 
50 mg po tid 
Enalapril 
5 mg po qd 
10–20 mg po qd 
40 mg po qd 
Ramipril 
2.5 mg po qd 
5 mg po qd 
10 mg po qd 
Lisinopril 
5 mg po qd 
10–20 mg po qd 
40 mg po qd 
Fosinopril 
10 mg po qd 
20 mg po qd 
40 mg po qd 
Perindopril 
4 mg po qd 
None 
8 mg po qd 
Quinapril 
10 mg po qd 
20 mg po qd 
20 mg po qd 
Angiotensin II Receptor Blockers 
Losartan 
25 mg po qd 
50 mg po qd 
100 mg po qd 
Candesartan 
4 mg po qd 
8–16 mg po qd 
32 mg po qd 
Ibresartan 
75 mg po qd 
150 mg po qd 
300 mg po qd 
Telmisartan 
40 mg po qd 
None 
80 mg po qd 
Valsartan 
80 mg po qd 
None 
160 mg po qd 
po = oral administration; qd = once daily; tid = three times daily 
Adapted from Kollmannsberger C, et al, CUAJ. 2007;Vol 1 (Issue 2 Suppl):S41–54. 


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APPENDIX E 
SORAFENIB PRESCRIBING INFORMATION 


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APPENDIX F 
STUDY DRUG INFORMATION 
1 
 
STUDY MATERIALS, STUDY DRUG STORAGE 
1.1  
Study Drug
Tivozanib is formulated for oral administration as a white opaque number 4 gelatin 
capsule containing 1.0 or 1.5 mg tivozanib.  The following dosage strengths will be made 
available: 
•
1.5 mg 
•
1.0 mg 
Sorafenib is formulated for oral administration as a round, biconvex, red film-coated 
tablet, debossed with the “Bayer cross” on one side and “200” on the other side.  The 
following dosage strength will be made available: 
•
200 mg 
The amount of study drug dispensed to the subject at the beginning of each dosing cycle 
will be sufficient to allow for 3 weeks (21 days) of consecutive once-daily dosing of 
tivozanib and 4 weeks (28 days) of consecutive twice-daily dosing of sorafenib.  Dosing 
compliance will be monitored at each clinic visit. 
1.2  
Study Drug Storage 
Tivozanib does not have any special storage requirements, and may be stored at room 
temperature in a dry place, in a secure location. Sorafenib is to be stored at room 
temperature (15o–25o C) in a dry place, in a secure location. 
2 
 
STUDY DRUG ADMINISTRATION 
2.1  
Route of Administration  
Tivozanib and sorafenib will be administered by the oral route.  
2.2  
Dosing Schedule 
 
Tivozanib:  Subjects will receive tivozanib one capsule once daily for 3 weeks followed 
by 1 week off study drug (1 cycle = 3 weeks on, 1 week off).  One cycle will be defined 
as 4 weeks of treatment.  Cycles will be repeated every 4 weeks.   
Sorafenib:  Subjects will receive sorafenib 2 tablets twice daily, beginning on Day 1 of 
Cycle 1 and then continuously for 4 weeks.  One cycle will be defined as 4 weeks of 
treatment.  Cycles will be repeated every 4 weeks.


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2.3  
Doses to be Administered 
 
 
 
 
Tivozanib:  1.5 mg/day  
 
 
 
 
Sorafenib:  400 mg twice daily 
2.4  
Dosing 
Tivozanib:  The prescribed oral daily dose of tivozanib is to be taken, preferably in the 
morning, with water.  Tivozanib should be taken at least 1 hour before or 2 hours after 
ingesting any food or other medications.  Grapefruit juice should not be ingested during 
the study.  On days of a scheduled clinic visit, the dose of tivozanib should be taken at the 
clinic after visit procedures are completed.  Treatment with tivozanib will continue if 
tolerated and in the absence of documented disease progression.  If a dose is vomited or if 
a dose is missed for any reason, the dose should not be made up.  If Day 1 of a cycle is 
delayed for any reason, the complete 21 days of tivozanib should be administered once 
the cycle is started.  Only one tivozanib capsule should be taken each day.
Sorafenib:  The prescribed twice-daily oral dose of sorafenib should be taken without 
food at least 1 hour before or 2 hours after ingesting any food or other medications.  On 
days of a scheduled clinic visit, the dose of sorafenib should be taken at the clinic after 
visit procedures are completed.  Treatment with sorafenib will continue if tolerated and in 
the absence of documented disease progression.  If a dose is vomited or if a dose is 
missed for any reason, the dose should not be made up.  If Day 1 of a cycle is delayed for 
any reason other than an adverse event, the complete 28 days of sorafenib should be 
administered.   
3   
DISPENSING, DISPOSAL AND INVENTORY OF STUDY DRUG 
1.
The investigator (or designee, ie, study pharmacist) at the site will be responsible for 
handling study drug and maintaining required documentation.  The investigator (or 
designee) will:   
•
Prepare the appropriate dose to be dispensed, as determined by the subject’s dose 
assignment. 
•
Record pertinent information regarding the doses of study drug prepared (eg, subject 
identification code, date of dispensing, number of doses/bottles dispensed, etc.) on 
the Drug Dispensing Log, or other appropriate study drug inventory.  This inventory 
will be maintained throughout the duration of the trial and will be periodically 
reviewed by a representative of the sponsor. 
•
Instruct the subject that all dispensed pill bottles must be returned at each follow-up 
visit, at which time a tablet/capsule count will be conducted to assure subject dosing 
compliance. 


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•
Inform the subject that at the completion of a subject’s participation in the 
trial, all partially used and empty pill bottles must be returned to the 
investigator (or designee) so that a final subject-dosing inventory may be 
conducted. 
2.
Throughout the conduct of this trial, the investigator (or designee) will maintain a careful 
inventory of all partially used and empty bottles of study drug.  Empty bottles may then 
be destroyed in an appropriate manner according to institutional policy.  Destruction of 
such bottles will be documented, and disposition records will later be reviewed by a 
representative of the sponsor.  All partially used bottles may be returned to the sponsor or 
designee (details to be provided), unless otherwise authorized in writing.   
Note: No other use of tivozanib study drug intended for use in this trial is authorized by 
the sponsor.  The investigator (or designee) will be responsible for the 
appropriate handling and disposition of residual study drug in partially used 
bottles.  Once returned to the investigator, capsules from partially used bottles 
will not be re-dispensed to another subject. 
3.  Periodically throughout and at the conclusion of the study, an inventory of unused bottles 
of study drug will be conducted by a representative of the sponsor.  At the completion of 
this trial, all unused study materials will be destroyed by the site or returned to the 
sponsor (or designee).  Destruction of study drug by the site can only occur after the 
sponsor (or designee) has collected the site’s SOP for drug destruction. 
4 
 
BOTTLE LABELS 
Study drug bottle labels will bear the appropriate label text for investigational agents, as required 
by governing regulatory agencies.
5 
 
RESUPPLY REQUESTS 
An IWRS will be used for management (shipping from depots to study sites, and 
dispensing to subjects).  Information regarding resupply via the IWRS will be in the 
IWRS study manual, provided separately.   


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APPENDIX G 
CLINICAL SYMPTOM AND ADVERSE EVENT GRADING SCALE 
CLINICAL ADVERSE EVENT GRADING 
Severity 
Grade 
Definition 
Mild 
1 
Awareness of symptom, but easily tolerated.  Usually transient 
requiring no special treatment; does not interfere with usual status or 
activities 
Moderate 
2 
May be ameliorated by simple therapeutic measures; may interfere 
with usual activities 
Severe 
3 
Incapacitating; unable to perform usual activities 
Life-threatening 
4 
Requires immediate intervention; need for emergency treatment 
Fatal 
5 
Resulting in the subsequent death of the subject 
Note:  In those cases where further definition of an event is provided by the NCI Common Terminology Criteria for 
Adverse Events (CTCAE, Version 4.03), please refer to that document for grading and severity information. 
*There are exceptions when an adverse event does not disappear upon discontinuation of the drug, yet 
drug relatedness clearly exists, eg, 1) tardive dyskinesia; 2) fixed drug eruptions. 


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APPENDIX H 
INTERNATIONAL METASTATIC RENAL CELL CARCINOMA 
DATABASE CONSORTIUM (IMDC) RISK MODEL 
Predefined Database Consortium risk factors: 
•
Anemia (hemoglobin concentration < lower limit of normal) 
•
Thrombocytosis (platelet count > upper limit of normal) 
•
Neutrophilia (neutrophil count > upper limit of normal) 
•
Hypercalcemia (corrected calcium concentration > upper limit of normal) 
•
Karnofsky performance status <80% * 
•
<1 year from initial diagnosis to first treatment with a targeted agent (VEGF or 
mTOR) 
Subject risk categories: 
•
Favorable risk: 
No risk factors 
•
Intermediate risk: One to two risk factors 
•
Poor risk: 
Three or more risk factors 
Heng DY, Xie W, Regan MM, et al. Prognostic factors for overall survival in patients with metastatic renal cell 
carcinoma treated with vascular endothelial growth factor-targeted agents: results from a large, multicenter study.
J Clin Oncol. 2009;27:5794–5799.  
Heng DYC, Xie W, Regan MM, et al. External validation and comparison with other models of the International 
Metastatic Renal-Cell Carcinoma Database Consortium prognostic model: a population-based study. Lancet Oncol. 
2013 February;14(2):141–148. 
Ko JJ, Xie W, Kroeger N, et al. The International Metastatic Renal Cell Carcinoma Database Consortium model as a 
prognostic tool in patients with metastatic renal cell carcinoma previously treated with first-line targeted therapy: a 
population-based study. Lancet Oncol. 2015 Mar;16(3):293-300. 
* Karnofsky performance status scale: 
100  - Normal; no complaints; no evidence of disease. 
90  - Able to carry on normal activity; minor signs or symptoms of disease. 
80  - Normal activity with effort; some signs or symptoms of disease. 
70  - Cares for self; unable to carry on normal activity or to do active work. 
60  - Requires occasional assistance, but is able to care for most of his personal needs. 
50  - Requires considerable assistance and frequent medical care. 
40  - Disabled; requires special care and assistance. 
30  - Severely disabled; hospital admission is indicated although death not imminent. 
20  - Very sick; hospital admission necessary; active supportive treatment necessary. 
10  - Moribund; fatal processes progressing rapidly. 
0  
- Dead 

SAP_001.pdf: 
AVEO Pharmaceuticals, Inc. 
AV-951-15-303 
Statistical Analysis Plan 
TP-GDO-WW-016-04 
CONFIDENTIAL 
Project Document Version No. 3.0 
Effective Date:  25 Nov 15 
Project Document Effective Date: 01 Oct 18 
Related to:  SOP-GDO-WW-019 
Page 1 of 32 
 PAREXEL International 
AVEO Pharmaceuticals, Inc. 
AV-951-15-303 
A Phase 3, Randomized, Controlled, Multi-Center, Open-Label Study to Compare 
Tivozanib Hydrochloride to Sorafenib in Subjects With Refractory Advanced Renal Cell 
Carcinoma 
Statistical Analysis Plan 
PAREXEL Project Number: 226044




AVEO Pharmaceuticals, Inc. 
AV-951-15-303 
Statistical Analysis Plan 
TP-GDO-WW-016-04 
CONFIDENTIAL 
Project Document Version No. 3.0 
Effective Date:  25 Nov 15 
Project Document Effective Date: 01 Oct 18 
Related to:  SOP-GDO-WW-019 
Page 3 of 32 
PAREXEL SIGNATURE PAGE 
This document has been approved and signed electronically on the final page by the 
following:
Signatory
Author  
Anne Blair 
Project Role: Biostatistics Lead  
Signatory 
Reviewer 
Martin Roessner 
Project Role: Biostatistics Reviewer
Beate Gerstbrein, PhD 
Project Role: Medical Writer Reviewer 


AVEO Pharmaceuticals, Inc. 
AV-951-15-303 
Statistical Analysis Plan 
TP-GDO-WW-016-04 
CONFIDENTIAL 
Project Document Version No. 3.0 
Effective Date:  25 Nov 15 
Project Document Effective Date: 01 Oct 18 
Related to:  SOP-GDO-WW-019 
Page 4 of 32 
TABLE OF CONTENTS 
1
INTRODUCTION ....................................................................................................... 7
2
STUDY OBJECTIVES ............................................................................................... 8
2.1 Primary Objective ................................................................................................. 8
2.2 Secondary Objectives ........................................................................................... 8
2.3 Tertiary Objective ................................................................................................. 8
3
INVESTIGATIONAL PLAN ..................................................................................... 9
3.1 Overall Study Design and Plan ............................................................................. 9
3.2 Efficacy and Safety Variables ............................................................................ 10
3.2.1 Efficacy Variables ..................................................................................... 10
3.2.2 Safety Variables ........................................................................................ 12
4
STATISTICAL METHODS ..................................................................................... 14
4.1 Data Quality Assurance ...................................................................................... 14
4.2 General Presentation Considerations .................................................................. 14
4.3 Study Subjects .................................................................................................... 16
4.3.1 Disposition of Subjects ............................................................................. 16
4.3.2 Protocol Deviations ................................................................................... 16
4.4 Analysis Populations .......................................................................................... 17
4.5 Demographic and Other Baseline Characteristics .............................................. 17
4.6 Treatment Compliance ........................................................................................ 18
4.7 Efficacy Evaluation ............................................................................................ 19
4.7.1 Analysis and Data Conventions ................................................................ 19
4.7.1.1 Multi-center Studies .................................................................... 19
4.7.1.2 Adjustments for Covariates ......................................................... 19
4.7.1.3 Handling of Dropouts or Missing Data ....................................... 20
4.7.1.4 Multiple Comparisons/Multiplicity ............................................. 21
4.7.1.5 Interim Analyses .......................................................................... 21
4.7.1.6 Examination of Subgroups .......................................................... 22
4.7.1.7 Exploratory Analyses .................................................................. 22
4.7.2 Primary Efficacy Variable – PFS .............................................................. 22
4.7.3 Secondary Efficacy Variables ................................................................... 24
4.8 Safety Evaluation ................................................................................................ 24
4.8.1 Extent of Exposure .................................................................................... 24
4.8.2 Adverse Events ......................................................................................... 25
4.8.3 Prior and Concomitant Medications ......................................................... 27
4.8.4 Clinical Laboratory Evaluation ................................................................. 28
4.8.5 Vital Signs, Physical Findings and Other Observations Related to Safety29
4.8.6 Safety Monitoring Committee .................................................................. 29
4.9 Determination of Sample Size ............................................................................ 30
4.10
Changes in the Conduct of the Study or Planned Analysis ...................... 31
5
REFERENCES .......................................................................................................... 31


AVEO Pharmaceuticals, Inc. 
AV-951-15-303 
Statistical Analysis Plan 
TP-GDO-WW-016-04 
CONFIDENTIAL 
Project Document Version No. 3.0 
Effective Date:  25 Nov 15 
Project Document Effective Date: 01 Oct 18 
Related to:  SOP-GDO-WW-019 
Page 5 of 32 
LIST OF ABBREVIATIONS 
ADI 
Actual Dose Intensity 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
BMI 
Body Mass Index 
BOR 
Best Overall Response 
BUN 
Blood Urea Nitrogen 
CI 
Confidence Interval 
cm 
centimeter(s) 
CMH 
Cochran-Mantel-Haenszel 
CR 
Complete Response  
CSR 
Clinical Study Report 
CT 
Computerized Tomography 
CTC 
Common Terminology Criteria 
CTCAE 
Common Terminology Criteria for Adverse Events 
DBP 
Diastolic Blood Pressure 
DoR 
Duration of Response 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
EMA 
European Medicines Agency 
EU 
European Union 
FDA 
Food and Drug Administration 
hCG 
human chorionic gonadotropin 
HR 
Hazard Ratio(s) 
ICH 
International Council for Harmonisation 
IDI 
Intended Dose Intensity 
IMDC 
International Metastatic Renal Cell Carcinoma Database 
Consortium 
INR 
International Normalized Ratio 
IRR 
Independent Radiological Review 
ITT 
Intent-to-treat 
IVRS 
Interactive Voice Response System 
IWRS 
Interactive Web Response System 
K-M 
Kaplan-Meier 
kg 
kilogram(s) 
LDH 
Lactase Dehydrogenase 
m 
meter(s) 
MA 
Markedly Abnormal 
MedDRA™ 
Medical Dictionary for Regulatory Activities 
mg 
milligram(s) 
mmHg 
millimeter(s) of mercury 
MRI 
Magnetic Resonance Imaging   


AVEO Pharmaceuticals, Inc. 
AV-951-15-303 
Statistical Analysis Plan 
TP-GDO-WW-016-04 
CONFIDENTIAL 
Project Document Version No. 3.0 
Effective Date:  25 Nov 15 
Project Document Effective Date: 01 Oct 18 
Related to:  SOP-GDO-WW-019 
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NA 
North America 
NCI 
National Cancer Institute 
NE 
Not Evaluable 
NMA 
Not Markedly Abnormal 
NRP 
Neuropilin 
OR 
Objective Response 
ORR 
Objective Response Rate 
OS 
Overall Survival 
p-y 
person-year(s) 
PD 
Progressive Disease 
PE 
Physical Examination 
PFS 
Progression-Free Survival 
PP 
Per-Protocol 
PR 
Partial Response  
PT 
Preferred Term or Prothrombin Time 
PTT 
Partial Thromboplastin Time 
RCC 
Renal Cell Carcinoma 
RDI 
Relative Dose Intensity 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
Serious Adverse Event 
SAF 
Safety (population) 
SAP 
Statistical Analysis Plan 
SBP 
Systolic Blood Pressure 
SD 
Stable Disease or Standard Deviation 
SI 
International System (of Units) 
SMC 
Safety Monitoring Committee 
SOC 
System Organ Class 
T3 
Triiodothyronine 
T4 
Thyroxine 
TEAE 
Treatment-Emergent Adverse Event 
TKI 
Tyrosine Kinase Inhibitor 
TSH 
Thyroid-stimulating Hormone 
US 
United States 
VEGF 
Vascular Endothelial Growth Factor 
VEGFR 
Vascular Endothelial Growth Factor Receptor 
WBC 
White Blood Cell 
WHO 
World Health Organization 


AVEO Pharmaceuticals, Inc. 
AV-951-15-303 
Statistical Analysis Plan 
TP-GDO-WW-016-04 
CONFIDENTIAL 
Project Document Version No. 3.0 
Effective Date:  25 Nov 15 
Project Document Effective Date: 01 Oct 18 
Related to:  SOP-GDO-WW-019 
Page 7 of 32 
1
INTRODUCTION 
Approximately 208,500 new cases of kidney cancer are diagnosed in the world each year, 
of which 40,000 new cases are diagnosed in North America and 63,300 new cases in the 
European Union (EU).  Renal cell carcinoma (RCC) accounts for 80%-85% of all 
malignant kidney tumors.  Advanced RCC is highly resistant to chemotherapy, and 
interleukin-2 and interferon-α have low levels of anti-tumor activity.  Recently, drugs 
that block the VEGF pathway such as sunitinib, sorafenib, bevacizumab, pazopanib, and 
axitinib have demonstrated significant anti-tumor activity in Phase 3 trials.  As a result, 
these drugs have become the standard of care for the treatment of subjects with advanced 
RCC. 
Tivozanib hydrochloride (tivozanib; previously known as AV-951 and as KRN951) is a 
novel and potent vascular endothelial growth factor (VEGF) receptor tyrosine kinase 
inhibitor (VEGFR TKI) that has demonstrated significant anti-tumor effects in 
pre-clinical experiments.  Other agents used for treatment of RCC such as sunitinib and 
sorafenib also inhibit multiple tyrosine kinases in addition to the VEGF receptor tyrosine 
kinase, but lead to off-target toxicities such as fatigue, hand-foot syndrome, stomatitis, 
and neutropenia.  The adverse event (AE) profile of tivozanib, however, demonstrates 
that it is a selective VEGF tyrosine kinase inhibitor, with minimal off-target toxicities. 
Based on these findings, tivozanib is expected to exhibit a broad anti-tumor spectrum of 
activities against various tumors by inhibiting angiogenesis and vascular permeability. 
TIVO-1 (AV-951-09-301) – a Phase 3, open-label, randomized, controlled, 
multi-national, multi-center, parallel-arm trial – was conducted to compare tivozanib to 
sorafenib in patients with advanced RCC.  The design of the study was such that patients 
with radiological evidence of progressive disease (PD) per investigator/local radiology 
assessment continued treatment until PD was verified by an independent radiologist, after 
which they were discontinued from study drug treatment and given the option to receive 
tivozanib under a separate extension protocol (AV-951-09-902).  In this study, 
superiority was shown for the primary endpoint, progression-free survival (PFS), based 
upon blinded independent radiological assessment (per Response Evaluation Criteria in 
Solid Tumors [RECIST] Version 1.0 definition).  Additional key efficacy endpoints were 
statistically significantly improved for tivozanib compared with sorafenib, and forest 
plots assessing the efficacy of tivozanib vs. sorafenib in multiple subgroups showed 
consistent benefit of tivozanib over sorafenib.  There was a slight difference in overall 
survival (OS), favoring the sorafenib randomized arm over the tivozanib randomized 
arm; however, an updated analysis of the second line efficacy data from study AV-951-
09-902 has revealed that second line efficacy of tivozanib in those patients who crossed 
over from sorafenib to tivozanib likely drives the discordance between the PFS and OS 
endpoints. 
Study AV-951-15-303 is a Phase 3, randomized, controlled, open-label, multi-center 
study comparing tivozanib to sorafenib in subjects with refractory advanced RCC.  As 
described above, tivozanib has demonstrated significant activity in the second line of 
therapy.  Sorafenib was chosen as a comparator for this Phase 3 trial because sorafenib is 
no longer the most commonly used first line VEGFR inhibitor used in advanced RCC. 


AVEO Pharmaceuticals, Inc. 
AV-951-15-303 
Statistical Analysis Plan 
TP-GDO-WW-016-04 
CONFIDENTIAL 
Project Document Version No. 3.0 
Effective Date:  25 Nov 15 
Project Document Effective Date: 01 Oct 18 
Related to:  SOP-GDO-WW-019 
Page 8 of 32 
This Statistical Analysis Plan (SAP) describes the statistical methods to be used during 
the reporting and analyses of data collected under protocol AV-951-15-303.   The 
planned analyses identified in this SAP may be included in the clinical study report 
(CSR), any regulatory submissions, or future manuscripts.  Post-hoc exploratory analyses 
not identified in this SAP may also be performed to further examine study data and will 
be clearly identified as such in the final CSR.     
This SAP is based upon the following study documents: 
•
Study Protocol, Version 3.0 (July 06, 2016)electronic Case Report Form (eCRF), 
Version 16.0 (March 24, 2016) 
The structure and content of this SAP provides sufficient detail to meet the requirements 
identified by the Food and Drug Administration (FDA), European Medicines Agency 
(EMA), and International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use (ICH)[1]. 
2
STUDY OBJECTIVES 
2.1
Primary Objective 
The primary objective of this study is as follows: 
•
To compare the PFS of subjects with refractory advanced RCC randomized to 
treatment with tivozanib or sorafenib as assessed by blinded independent 
radiological review (IRR) of computerized tomography (CT) or magnetic 
resonance imaging (MRI) 
2.2
Secondary Objectives 
The secondary objectives of this study are as follows: 
•
To compare the OS of subjects randomized to treatment with tivozanib or 
sorafenib 
•
To compare objective response rate (ORR) and duration of response (DoR) of 
subjects randomized to treatment with tivozanib or sorafenib  
•
To compare the safety and tolerability of tivozanib and sorafenib 
2.3
Tertiary Objective 
The tertiary objective of this study is as follows: 
•
To explore any relationship between tivozanib and sorafenib drug levels and 
activity 
•
To explore any relationship between tivozanib and sorafenib drug levels and 
adverse events (AEs) 


AVEO Pharmaceuticals, Inc. 
AV-951-15-303 
Statistical Analysis Plan 
TP-GDO-WW-016-04 
CONFIDENTIAL 
Project Document Version No. 3.0 
Effective Date:  25 Nov 15 
Project Document Effective Date: 01 Oct 18 
Related to:  SOP-GDO-WW-019 
Page 9 of 32 
3
INVESTIGATIONAL PLAN 
3.1
Overall Study Design and Plan 
This is a Phase 3, open-label, randomized, controlled, multi-national, multi-center, 
parallel-arm study comparing tivozanib to sorafenib in subjects with refractory advanced 
RCC.  The study is designed to compare the PFS, OS, ORR, DoR, safety, and tolerability 
of tivozanib and sorafenib.  Approximately 322 subjects with refractory advanced RCC 
are planned to participate in this study at approximately 160-190 sites.  Once informed 
consent has been obtained and all eligibility criteria have been met (refer to Sections 6.1 
and 6.2 of the study protocol for detailed inclusion/exclusion criteria), subjects will be 
randomized 1:1 using an Interactive Web Response System (IWRS).  They will be 
randomized to treatment with tivozanib or sorafenib, stratified by International Metastatic 
Renal Cell Carcinoma Database Consortium (IMDC) risk category (favorable; 
intermediate; poor) and prior therapy (two prior VEGFR TKIs; a prior checkpoint 
inhibitor [PD-1 or PD1 L inhibitor] plus a prior VEGFR TKI; a prior VEGFR TKI plus 
any other systemic agent), and must begin treatment within 14 days after randomization.  
It is anticipated that enrollment to this study will be completed in approximately 15 
months.   
Tivozanib will be administered orally, at a dose of 1.5 mg/day, beginning on Day 1 of 
Cycle 1. Subjects will receive tivozanib once daily for 3 weeks followed by 1 week off 
study drug (1 cycle = 3 weeks on, 1 week off). One cycle will be defined as 4 weeks of 
treatment. Cycles will be repeated every 4 weeks. Tivozanib should be taken at least 1 
hour before or 2 hours after ingesting any food or other medications.  
Sorafenib will be administered orally, at an initial dose of 400 mg (two 200 mg tablets) 
twice daily continuously, beginning on Day 1 of Cycle 1. One cycle will be defined as 4 
weeks of treatment. Cycles will be repeated every 4 weeks.  Sorafenib should be taken 
without food at least 1 hour before or 2 hours after ingesting any food or other 
medications. 
Subjects with documented stable disease or an objective response may continue to 
receive therapy at the same dose and schedule until disease progression or unacceptable 
toxicities occur, or if other withdrawal criteria are met.  Regardless of the duration of the 
study treatment, all subjects who develop early progressive disease (PD) per RECIST 
Version 1.1[2] prior to response evaluation will be considered to have progressed on 
study.  Once discontinued, all subjects are to be followed for evidence of delayed effects 
of study drug for a minimum of 30 days from the last dose of study drug. After the 30-
Day Follow-up visit, subjects will be contacted once every 3 months by the sites to 
collect long-term survival data. Additional contacts may be made to support key analyses, 
such as the analysis of overall survival at the time of the final PFS analysis, and the final 
analysis of OS. 


AVEO Pharmaceuticals, Inc. 
AV-951-15-303 
Statistical Analysis Plan 
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Subjects experiencing unacceptable toxicities will be discontinued from further study 
treatment. Subjects with radiological evidence of progressive disease (per RECIST 
Version 1.1) per investigator/local radiology assessment should continue treatment until 
progressive disease is verified by an independent radiologist. An independent safety 
monitoring committee (SMC) will monitor the safety data from this study on a periodic 
basis. 
Safety assessments are performed on an ongoing basis.  The following procedures and 
evaluations can be collected at unscheduled visits as needed:  electrocardiogram (ECG), 
physical examination, Eastern Cooperative Oncology Group (ECOG) performance status, 
hematology, serum chemistry, coagulation parameters, thyroid function tests, urinalysis, 
pregnancy tests, vital signs, tumor assessment, and survival status. Data from 
unscheduled assessments of the safety endpoints listed above will be included in data 
listings but not table summaries.  For a complete schedule of planned assessments, please 
refer to Table 1 and/or Section 7 of the study protocol.  
3.2
Efficacy and Safety Variables 
3.2.1
Efficacy Variables 
Tumor response will be assessed using RECIST v1.1 criteria.  Subjects will undergo 
assessments at screening and every 8 weeks following Cycle 1, Day 1 until radiological 
disease progression is documented and confirmed by independent radiology review.  
Evaluable subjects are those who receive at least 2 cycles of study drug.  
Best overall response (BOR) is determined once all assessments from randomization until 
disease progression or death are recorded.  In general, it is the best response across all 
assessments; however, confirmation of complete response (CR), partial response (PR), 
and stable disease (SD) will also be used in BOR determination.  To confirm CR or PR 
changes in tumor measurements must be confirmed by repeat assessments that should be 
no less than 4 weeks (28 days) after the criteria for response are first met.  To confirm SD, 
it must have occurred at least 8 weeks from Cycle 1, Day 1; otherwise, BOR will depend 
on subsequent assessments. 
All subjects will be followed until death from any cause (unless the subject is lost to 
follow-up, withdraws consent for the entire study, or the sponsor terminates the study 
early).  After the 30-Day Follow-up visit, subjects will be contacted once every 3 months 
by the site to collect long-term survival data.  For subjects with ongoing objective 
response or disease stabilization at the time of treatment discontinuation, or for subjects 
who discontinue for reasons other than radiological evidence of progressive disease, 
tumor assessments will continue to be collected every 2 months during the first year 
(beginning from the date of the last scan performed prior to treatment discontinuation), 
every 3 months during the second year, and every 6 months thereafter until disease 
progression is confirmed by independent radiology review or the start of another anti-
tumor therapy that includes anti-cancer surgery/procedure, anti-cancer radiotherapy, and 
anti-cancer systemic therapy. 


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Primary Efficacy Endpoint 
PFS is defined as the time from randomization date to the first date of radiological PD or 
death date (due to any reason), whichever event is earlier.  PFS in months will be 
calculated as:  (first event date − randomization date + 1) * (12/365.25).  Censoring will 
occur as follows: 
•
If there are no tumor assessments after randomization, PFS will be censored on 
the date of randomization. 
•
If a subject is known to be alive and progression-free, PFS will be censored on the 
day of the last tumor assessment. 
•
If a subject is given anti-tumor treatment (anti-cancer surgery/procedure, anti-
cancer radiotherapy, and anti-cancer systemic therapy other than the study 
treatment) prior to PD or death, PFS will be censored on the date of the last tumor 
assessment prior to the start date of the anti-tumor treatment. 
•
If treatment follow-up ceases prior to objective PD, PFS will be censored on the 
date of the last tumor assessment.  
Secondary Efficacy Endpoints 
OS is defined as the time from the date of randomization to the date of death (due to any 
reason).  OS in months will be calculated as:  (death date − randomization date + 1) * 
(12/365.25).  Censoring will occur as follows: 
•
If there are no tumor assessments after randomization, OS will be censored on the 
date of randomization. 
•
If there is no confirmation of death, OS will be censored on the date the subject is 
last known to be alive. 
ORR is defined as the proportion of subjects with best overall response (BOR) of 
confirmed CR or confirmed PR [i.e. objective response (OR)], according to the RECIST 
1.1 among subjects with measurable disease at baseline.    
DoR is defined as the time from the first date of OR to first date of radiological PD.  This 
will only apply to subjects with confirmed CR or confirmed PR and will be calculated as:  
(first event date – first OR date + 1) * (12/365.25).  Censoring will occur as follows: 
•
If a subject is known to be alive and progression-free, DoR will be censored on 
the day following the date of the last tumor assessment. 
•
If a subject dies of a cause known to be non-cancer related, DoR will be censored 
on the date of the last progression-free tumor assessment. 
•
If a subject dies of an unknown cause in the absence of documented PD, DoR will 
be censored on the date of the last tumor assessment. 
•
If a subject is given anti-tumor treatment (anti-cancer surgery/procedure, anti-
cancer radiotherapy, and anti-cancer systemic therapy other than the study 


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treatment) prior to PD or death, DoR will be censored on the date of the last 
progression-free tumor assessment prior to the start date of the anti-tumor 
treatment. 
•
If treatment follow-up ceases prior to objective PD, DoR will be censored on the 
date of last progression-free tumor assessment.  
Tertiary Efficacy Endpoint 
The relationship between tivozanib and sorafenib drug levels and activity will be 
explored through tumor response assessment using RECIST 1.1 criteria. 
The relationship between and tivozanib and sorafenib drug levels and adverse events will 
be explored through summaries of adverse events related to the study drugs. 
3.2.2
Safety Variables 
Safety endpoints include study drug exposure, adverse events, laboratory parameters, 
vital signs, electrocardiogram (ECG), ECOG performance status, concomitant 
medications, and physical examination. 
Study Drug Exposure 
Duration of treatment (i.e. exposure) for both tivozanib and sorafenib is defined as the 
time from the date of the first dose of study treatment to the date of the last dose of study 
treatment.  Duration of treatment is calculated as:  (last dose date – first dose date) + 1.  
Adverse Event (AE) 
Information regarding the occurrence of AEs will be collected throughout participation in 
this study, starting from the time the subject signs the informed consent form until a 
period of 30 days after the last dose of study drug.  AEs will be coded by system organ 
class (SOC) and preferred term (PT) using the Medical Dictionary for Regulatory 
Activities (MedDRA™) Dictionary (Version 18.0 or later).  Severity will be graded 
according to the National Cancer Institute (NCI) Common Terminology Criteria for 
Adverse Events (CTCAE) Version 4.03.  AEs leading to death or study treatment 
discontinuation, treatment-related AEs, serious adverse events (SAEs), and treatment-
emergent adverse events (TEAEs) will be considered with special attention. 
A TEAE is defined as an AE (identified by PT) that begins or that worsens in severity 
after at least one dose of study treatment has been administered. That is, an AE is 
considered treatment-emergent if either of the following is met: 
•
The event begins on or after the first day of study treatment and before 30 days 
after the last dose of study treatment plus it was never recorded prior to the start 
of study treatment 
•
The event was recorded or began prior to the start of study treatment but increased 
in NCI CTCAE v4.03 grade on or after the first dose of study treatment 


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Laboratory Parameters 
The following laboratory parameters will be collected in accordance with the schedule of 
assessments as specified in Table 1 of the study protocol: 
•
Hematology:  complete blood count with differential and platelet count 
•
Serum Chemistry:  sodium, potassium, chloride, bicarbonate (optional), blood 
urea nitrogen (BUN), creatinine, glucose, total bilirubin, direct bilirubin, aspartate 
aminotransferase (AST), alanine aminotransferase (ALT), lactase dehydrogenase 
(LDH), alkaline phosphatase, calcium, magnesium, phosphorus, albumin, amylase, 
lipase, and total protein 
•
Coagulation:  prothrombin time (PT) and/or international normalized ratio (INR), 
and partial thromboplastin time (PTT) 
•
Thyroid Function:  Free T4 (thyroxine), and thyroid stimulating hormone (TSH) 
levels.  Total T3 (triiodothyronine) is optional 
•
Urinalysis:  protein, glucose, ketones, urobilinogen, occult blood, microscopic 
sediment evaluation, and 24-hour urine test (required only when protein is at least 
4+) 
•
Pregnancy:  serum ß-human chorionic gonadotropin (hCG) for premenopausal, 
non-sterilized females 
Vital Signs 
Vital sign assessments will be collected in accordance with the schedule of assessments 
as specified in Table 1 of the study protocol after a subject has been sitting for 5 minutes.  
They will include measurements of diastolic and systolic blood pressure (mmHg), heart 
rate (beats per minute), respiration rate (breaths per minute), and body temperature 
(Celsius). 
Electrocardiogram (ECG) 
A 12-lead ECG will be performed in accordance with the schedule of assessments as 
specified in Table 1 of the study protocol after a subject has been supine for 
approximately 10 minutes.  This assessment will include results categorized as normal; 
abnormal, not clinically significant; abnormal, clinically significant; or unevaluable. 
ECOG Performance Status 
In accordance with the schedule of assessments as specified in Table 1 of the study 
protocol, ECOG performance status will be recorded as follows: 


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0 = Fully active, able to carry on all pre disease performance without restriction. 
1 = Restricted in physically strenuous activity but ambulatory and able to carry out work   
      of a light or sedentary nature, e.g., light house work, 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 = Death 
Concomitant Medications 
Any medication that a subject takes other than tivozanib or sorafenib during the duration 
of treatment is considered a concomitant medication.  Information regarding the usage of 
concomitant medications will be collected throughout participation in this study, starting 
from the time the subject signs the informed consent form until a period of 30 days after 
the last dose of study drug.  For each concomitant medication taken during the study, the 
generic component will be identified using the World Health Organization Drug (WHO 
Drug) Dictionary.   
Physical Examination 
A complete physical examination (PE) will be performed at screening by a physician or 
staff member who is qualified to perform such examinations.  The complete PE will 
entail a thorough review of all body systems, including weight (kg) and height (cm).  The 
remaining PE assessments will be directed PEs, but must include weight (kg).  They will 
be done in a targeted manner, covering body systems related to the subject’s disease or 
relevant findings in the complete PE. 
4
STATISTICAL METHODS 
4.1
Data Quality Assurance 
All tables, figures, and data listings to be included in the report will be independently 
checked for consistency, integrity and in accordance with standard PAREXEL 
procedures. 
4.2
General Presentation Considerations 
‘Baseline’ is defined as the last observation on or before Cycle 1 Day 1. Baseline 
assessments should occur within 7 days of Cycle 1 Day 1.  ‘End of Treatment’ is defined 
as the last available observation up to 7 days after the last dose of study treatment.  ‘End 
of Study’ is defined as the last available observation after ‘End of Treatment’. 


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Durations are calculated as the stop date minus the start date plus one. 
For elapsed time (e.g. time since the initial diagnosis) if the reference date is on or after 
the event date, then the elapsed time is the reference date minus the event date plus one.  
If the reference date is before the event date then the elapsed time is the reference date 
minus the event date. 
Unscheduled assessments (laboratory data, ECG, or vital signs associated with non-
protocol clinical visits or obtained in the course of investigating or managing adverse 
events) will be included in listings, but not summaries. If more than one laboratory value 
is available for a given visit, the first valid observation will be used in summaries and all 
observations will be presented in listings. If it is not possible to determine which is the 
first measurement due to missing times then the average of all measurements for that time 
point will be used as the value for that time point. 
Continuous data will be summarized in terms of the mean, standard deviation (SD), 
median, minimum, maximum, and number of observations, unless otherwise stated. 
Continuous data that are expected to be skewed will be presented in terms of the 
maximum, upper quartile, median, lower quartile, minimum, and number of observations.  
The minimum and maximum will be reported to the same number of decimal places as 
the raw data recorded in the database.  The mean, median, lower quartile, and upper 
quartile will be reported to one more decimal place than the raw data recorded in the 
database.  The SD will be reported to two more decimal places than the raw data recorded 
in the database.  In general, the maximum number of decimal places reported shall be 
four for any summary statistic. 
Categorical data will be summarized in terms of the number of subjects providing data at 
the relevant time point (n), frequency counts, and percentages.  Any planned collapsing 
of categories will be detailed in the corresponding sections of this SAP and within the 
data displays.  Percentages will be presented to one decimal place.  Percentages will not 
be presented for zero counts.  Percentages will be calculated using n as the denominator. 
Changes from baseline in categorical data will be summarized using shift tables where 
appropriate. 
P-values greater than or equal to 0.001, in general, will be presented to three decimal 
places.  P-values less than 0.001 will be presented as “<0.001” and p-values greater than 
0.999 will be presented as “>0.999”.  
Confidence intervals will be presented to one more decimal place than the raw data. 
All report outputs will be produced using SAS® version 9.2 or a later version in a secure 
and validated environment.  Each report output will be provided to the sponsor in a single 
Microsoft Word document.   


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4.3
Study Subjects 
4.3.1
Disposition of Subjects 
A clear accounting of the disposition of all subjects who enter the study will be provided, 
from screening to end of study participation.  Summaries of subject disposition presented 
by treatment arm and overall will be provided as follows: 
•
Number and percentage of subjects randomized 
•
Number and percentage of subjects randomized by region  
•
Number and percentage of subjects treated (i.e. received at least one dose of study 
drug treatment) 
•
Number of subjects in the analysis populations 
•
Number and percentage of subjects who withdrew early from the study (including 
reasons for early withdrawal) 
•
Number and percentage of subjects who withdrew early from treatment (including 
reasons for early withdrawal) 
By-subject listings of randomization details, visit dates, and withdrawal details (including 
reason for discontinuation and duration of treatment prior to discontinuation) will also be 
provided. 
4.3.2
Protocol Deviations 
Major protocol deviations are defined as those deviations from the protocol likely to have 
an impact on the perceived efficacy and/or safety of study treatments.  The impact of 
major protocol deviations on the efficacy and/or safety results will be investigated by 
assessing the robustness of the study results and conclusions to the choice of analysis 
population (see Section 4.4 for descriptions of analysis populations), both including and 
excluding data potentially affected by major protocol deviations.   
A subject will be classified as having a protocol deviation if one incurs an event 
belonging to any one of the following categories: 1) violation of the inclusion/exclusion 
criteria; 2) taking prohibited medications or treatments; 3) treatment misallocation; 4) 
violation of discontinuation criteria; 5) error in procedure and tests; and 6) missed visits 
(including procedures and tests).  
Major protocol deviations and any action to be taken regarding the exclusion of subjects 
are defined in the study protocol deviation specifications.  The final determination of 
major protocol deviations and the exclusion of subjects from any of the analysis 
populations will be made prior to database lock. 
A summary of the number and percentage of subjects with a major protocol deviation by 
treatment arm as well as by type of deviation will be provided. Also, a by-subject listing 
of major protocol deviations will be provided.  


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4.4
Analysis Populations 
•
The intent-to-treat (ITT) population will consist of all randomized subjects; this 
population will be used for efficacy analysis, including primary endpoints. 
Subjects will be analyzed as randomized. 
•
The per-protocol (PP) population is defined as all randomized subjects who 
received at least two cycles (8 weeks) of protocol treatment, had no major 
protocol deviations that will confound the effects of treatment, and met all 
eligibility criteria. The PP population will be used as a sensitivity analysis for the 
assessment of the primary efficacy endpoint, and subjects will be analyzed as 
treated. 
•
The safety (SAF) population will include all subjects who received at least one 
dose of either study drug.  Subjects will be analyzed as treated.  
The efficacy summaries and analyses will be based on the ITT population.  In the event 
that a subject is allocated the incorrect study treatment as per the study randomization 
list, subjects will be summarized and analyzed ‘as randomized’ (i.e. by randomized 
treatment arm).  In the event that a subject is stratified incorrectly, ‘randomized stratum’ 
will be used rather than ‘actual stratum’. 
The safety summaries and analyses will be based on the SAF population.  In the event 
that a subject is allocated the incorrect study treatment as per the study randomization 
list, subjects will be summarized and analyzed ‘as treated’ (i.e. by allocated treatment 
arm). 
A by-subject listing of analysis population details will be provided.  This listing will be 
presented 
by 
treatment 
arm 
and 
will 
include: 
center, 
subject 
identifier, 
inclusion/exclusion flag for each population, and reason for exclusion from each 
population.   
4.5
Demographic and Other Baseline Characteristics 
The following demographic and baseline characteristics will be summarized for subjects 
in the ITT population by treatment arm: 
•
Age at time of informed consent (in years, as a continuous variable) 
•
Age categorization (<65, >= 65 years) 
•
Gender (Male, Female) 
•
Race (White, Black/African American, Asian, American Indian/Alaska Native, 
Hawaiian Native/Other Pacific Islander, Unknown, Other, Decline to State) 
•
Ethnicity (Hispanic or Latino, Not Hispanic or Latino, Unknown, Decline to 
State) 
•
Geographic region [North America (NA), European Union (EU), Rest of World] 
•
Weight at screening (in kilograms) 


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•
Height at screening (in centimeters) 
•
BMI at screening (in kg/m2) calculated using weight and height at screening 
•
Baseline systolic blood pressure (<=140 mmHg, >140 mmHg) 
•
Baseline diastolic blood pressure (<=90 mmHg, >90 mmHg) 
•
IMDC risk category (Favorable, Intermediate, Poor) 
•
Prior therapy (Two Prior VEGFR TKIs, Prior Checkpoint Inhibitor Plus VEGFR 
TKI, Prior VEGFR TKI Plus Other Systemic Agent) 
•
Baseline Eastern Cooperative Oncology Group (ECOG) performance status (0, 1) 
•
Primary diagnosis:  
o
Time from initial diagnosis to randomization (in months) 
o
Time from most recent relapse or staging to randomization (in months) 
o
Pathological diagnosis (Clear Cell, Clear Cell Component, Other) 
o
Diagnosis confirmation method (Histology, Cytology, Other) 
o
Stage at screening [Stage IV (metastatic), Local Recurrence] 
o
Metastatic site location 
o
Type of metastases (Multiple Metastases, Solitary Metastases, No 
Involvement, Unknown) 
•
Primary disease:  
o
Number of metastatic sites per subject 
o
Prior radiotherapy (Yes, No) 
o
Prior chemotherapy setting (Neo-adjuvant, Adjuvant, 
Metastatic/Unresectable Therapy, Other, Unknown) 
o
Prior nephrectomy (Complete Nephrectomy, Partial Nephrectomy, Other) 
Since age is part of the inclusion criteria, age will be calculated as the number of 
complete years between a subject’s birth date and the date of informed consent. 
4.6
Treatment Compliance 
Compliance with study treatment will be assessed via relative dose intensity (RDI).  
Relative dose intensity is defined as 100% times the actual dose intensity (ADI) divided 
by the intended dose intensity (IDI).  Actual dose intensity for a subject is defined as the 
total dose received over all cycles divided by the sum of the lengths of all cycles in days.  
The intended dose intensity is the total dose assigned over all cycles divided by the sum 
of the intended lengths of all cycles in days.  The assigned dose for a cycle for tivozanib 
is 1.5 mg/day taken for 3 weeks with 1 week off of study drug.  The assigned dose for a 
cycle for sorafenib is 400 mg twice a day continuously for 4 weeks.   
For example, for two cycles of treatment, the intended dose intensity(IDI) for sorafenib 
would be: 
400 mg* 2 * 28 days * 2 / 56 days  = 800 mg 
Summaries of ADI, IDI, and RDI will be presented by treatment arm across all cycles as 
well as for each cycle.   
A by-subject listing of study treatment compliance data will also be provided, containing 
the date of randomization, the date of last dose of study treatment, and the calculated RDI. 


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4.7
Efficacy Evaluation 
4.7.1
Analysis and Data Conventions 
This study is designed to test for superiority.  The null hypothesis will be that there is no 
difference between tivozanib and sorafenib in median PFS.  The alternative hypothesis 
will be that there is a difference.  Symbolically, this is expressed as follows: 
H0:  mPFStivozanib ≤ mPFSsorafenib
Ha:  mPFStivozanib > mPFSsorafenib
A one-sided, log-rank test stratified for IMDC risk category (favorable vs. intermediate 
vs. poor) and prior therapy (two prior VEGFR TKIs vs. a prior checkpoint inhibitor plus 
a prior VEGFR TKI vs. a prior VEGFR TKI plus any other systemic agent) at a 
significance level of α = 0.025 will be used to test this hypothesis. 
Estimates of the hazard ratio (HR) for treatment and the corresponding 95% CI will also 
be presented.  They will be estimated using the stratified Cox proportional hazards  
model with sorafenib as the reference group and stratification factors IMDC risk category 
and prior therapy. 
4.7.1.1
Multi-center Studies 
For the purpose of the summaries and analyses mentioned in this SAP, the term ‘Center’ 
will be used to define each investigator site. 
All centers will be pooled together in the efficacy analyses.  If the results reveal impact of 
the centers, then ad hoc analyses will be performed.  In that case, the centers may be 
grouped by geographic regions (see Section 4.5) and evaluation of the consistency of 
treatment effects across geographic regions may be performed. 
4.7.1.2
Adjustments for Covariates 
The potential influences of baseline characteristics and stratification factors on the 
primary PFS endpoint will be evaluated.  These factors include the following: 
•
Age categorization (<65, >= 65 years) 
•
Race (White, Non-white) 
•
Gender (Male, Female) 
•
Baseline Eastern Cooperative Oncology Group (ECOG) performance status (0, 1) 
•
Time from initial diagnosis to randomization (< 1 year, >=1 year) 
•
Geographic region [North America (NA), European Union (EU), Rest of World] 


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•
IMDC risk category (Favorable, Intermediate, Poor) 
•
Prior therapy (Two Prior VEGFR TKIs, Prior Checkpoint Inhibitor Plus VEGFR 
TKI, Prior VEGFR TKI Plus Other Systemic Agent) 
•
Number of metastatic sites involved (1, >=2) 
•
Baseline systolic blood pressure (<=140 mmHg, >140 mmHg)Baseline diastolic 
blood pressure (<=90 mmHg, >90 mmHg) 
To assess the robustness of study conclusions to the choice of covariates, a sensitivity 
analysis will be performed.   
4.7.1.3
Handling of Dropouts or Missing Data 
In general, imputed partial dates will not be used to derive study day, duration (e.g., 
duration of adverse events), or elapsed time variables.  In addition, imputed dates are not 
used for deriving the last contact date in the overall survival analysis dataset. 
Imputed dates will not be displayed in listings unless otherwise stated. 
The partial date imputation will follow ADaM conventions. The ADaM approach is to 
populate the numeric date variables with the imputed date and add a flag variable to the 
dataset that indicates the level of imputation.  
The flag variable can contain the values: blank, 'D', 'M', 'Y'.  
blank: indicates that no imputation was done 
•
D='Day': indicates that the day portion of the date is imputed 
•
M='Month': indicates that the month and day portions of the date are imputed 
•
Y='Year': indicates that the entire date (year, month, and day) is imputed 
Imputing partial AE and prior/concomitant medication start dates: 
a) If the year is unknown, the date will not be imputed and will be assigned a 
missing value. 
b) If the month is unknown, then: 
1. If the year matches the first dose date, then impute to the month and day of 
the first dose date. 
2. Otherwise, assign ‘January’. 
c) If the day is unknown, then: 
1. If the month and year match the first dose date, then impute to the day of 
the first dose date. 
2. Otherwise, assign ‘01’. 


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Imputing partial AE and prior/concomitant medication stop dates: 
a) If the year is unknown, the date will not be imputed and will be assigned a 
missing value. 
b) If the month is unknown, then assign ‘December’. 
c) If the day is unknown, then impute to the last day of the month. 
Imputing partial death dates: 
a) If the month and/or year are unknown, the death date will not be imputed and the 
subject will be censored for overall survival at the last known date alive. 
b) If the day is missing, then assign ‘01’. 
c) If imputing the first day of the month results in a negative overall survival time, 
the subject will be censored for overall survival at the randomization date. 
A subject data listing will be provided showing all subjects with missing values for the 
primary endpoint.  For these subjects, the listing will provide all observed data relating to 
the primary endpoint (i.e. all measurements recorded prior to the missing value, any 
measurements recorded after the missing value, important baseline characteristics, the 
recorded reason for study discontinuation, and the date of study discontinuation).  The 
listing will also provide the imputed date(s) used in the primary analysis. 
4.7.1.4
Multiple Comparisons/Multiplicity 
There will be no adjustment for multiplicity. PFS with one treatment contrast (tivozanib 
vs. sorafenib) is the only primary analysis defined for this study.  The secondary analyses 
are simply intended to provide supportive evidence relating to the primary analysis, 
therefore, all efficacy endpoints will be assessed without adjustment for multiple 
comparisons. 
4.7.1.5
Interim Analyses 
An interim analysis will be performed after 128 PFS events have been observed. The 
interim analysis will look into the study’s futility with PFS as the efficacy evaluation 
endpoint. This utilizes a Lan-DeMets spending-type function with an O’Brian-Fleming 
stopping boundary and estimated two-sided beta (Type II error) of 1.2% spent during this 
interim look. A planned futility analysis will also be performed. 
This interim and futility analyses will be performed by an independent statistician. The 
independent statistician will evaluate and interpret the results of the interim and futility 
analyses and will provide corresponding recommendation.  The recommended outputs for 
this reporting effort will be listed in a separate document. 


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4.7.1.6
Examination of Subgroups 
The uniformity of the treatment effect for the primary efficacy variable will be examined 
for the following subgroups: 
1. Age categorization (<65 years, >=65 years) 
2. Gender (Male, Female) 
3. Race (White, Non-White) 
4. Baseline Eastern Cooperative Oncology Group (ECOG) performance status (0, 1) 
5. Time from initial diagnosis to randomization (< 1 year, >=1 year) 
6. Geographic region [North America (NA), European Union (EU), Rest of World] 
7. IMDC risk category (Favorable, Intermediate, Poor) 
8. Prior therapy (Two Prior VEGFR TKIs, Prior Checkpoint Inhibitor Plus VEGFR 
TKI, Prior VEGFR TKI Plus Other Systemic Agent) 
9. Number of metastatic sites involved (1, >=2) 
10. Baseline systolic blood pressure (<=140 mmHg, >140 mmHg) 
11. Baseline diastolic blood pressure (<=90 mmHg, >90 mmHg) 
The homogeneity of the treatment effect across subgroups will be investigated using 
graphical method showing the median treatment effect and 95% confidence interval (CI) 
within each subgroup. Summaries of the primary efficacy variable by treatment arm and 
subgroup will be produced.  
4.7.1.7
Exploratory Analyses  
In order to evaluate if the timing of post-baseline radiological scan influenced the 
primary outcome, the time from randomization to post-radiological scan will be 
calculated and an exploratory analyses will be conducted. Mean and standard deviation of 
radiological scan time will be presented by treatment arms and cycle time. Long-Rank 
test will be used to test if cumulative percentages (survival curve) are equal (median time 
to each cycle from randomization) by treatment arms.  
4.7.2
Primary Efficacy Variable – PFS  
Primary Analysis on PFS 
The primary variable for the assessment of efficacy is PFS, as defined in Section 3.2.1 of 
this SAP. 
PFS based on IRR will be summarized for the ITT population using the Kaplan-Meier 
method.  These summaries will include 1- and 2-year survival probabilities along with 
corresponding 95% CIs.  Graphical displays (i.e. K-M plots), where appropriate, will also 
be produced. 


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Median event times and corresponding two-sided 95% CIs for the medians will be 
provided for PFS.  A stratified log-rank test (one-sided, α=0.025) as well as hazard ratios 
and corresponding 95% CIs from a stratified Cox proportional hazard model, both 
adjusting for IMDC risk category and prior therapy, will be used to compare PFS 
between the two treatment arms.  
When determining PFS, the recorded date of progression (defined as first time at which 
progression can be declared) will be used.  For progression due to the presence of a new 
lesion, the date of progression is the first date that the new lesion was observed.  If 
multiple assessments based on the sum of target lesion measurements are done at 
different times, the date of progression is the date of the last observation or radiological 
assessment of target lesions that shows a predefined increase in the sum of the target 
lesion measurements. 
The robustness of the study results to the choice of baseline covariates will be 
investigated as described in Section 4.7.1.2.   In addition, the homogeneity of the 
treatment effect for important subgroups will be investigated as described in Section 
4.7.1.6.  
A by-subject listing of the primary efficacy data will be provided. 
Sensitivity Analyses on PFS 
Sensitivity Analysis #1 will be done using the investigator assessment of response, 
adding in as events any clinical PDs specified by the investigator.  A clinical PD is 
defined to be treatment failure not meeting the criteria for progressive disease but 
considered by the investigator to require removal of the subject from the study.  This 
analysis will be conducted using the ITT and PP populations.   
Sensitivity Analysis #2 will consider the initiation of new anti-tumor treatment to be an 
event.  In this analysis, any death or PD will also be events, even those that occur after 
two or more missed tumor assessments.  This analysis will be conducted using only the 
ITT population.   
Sensitivity Analysis #3 will be similar to Sensitivity Analysis #2, with the addition of 
discontinuation of therapy considered an event as well.  Again, this analysis will be 
conducted using only the ITT population. 
Sensitivity Analysis #4 will be conducted to assess the impact of missed or not evaluable 
(NE) tumor assessments.  This analysis will use the IRR assessments and backdate any 
PD events that occur immediately after missing or NE assessments.  If the PD occurs 
immediately after NE assessment (or series of NE assessments), the PD date will be the 
date of the first NE assessment preceding the PD.  If the PD occurs immediately after a 
missed assessment (or series of missed assessments), the PD date will be the date of the 
first missed assessment preceding the PD.  This analysis will use the ITT population. 


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All sensitivity analyses will use the same statistical methods as the primary analysis.   
Exploratory Analysis on PFS 
An exploratory analysis of PFS based on IRR will be summarized for the SAF population 
using the Kaplan-Meier method.  This analysis will examine PFS for all subjects who 
were randomized and administered at least one dose of the study drug.  This analysis will 
use the same statistical methods as the primary analysis. 
4.7.3
Secondary Efficacy Variables 
Overall Survival 
The first secondary analysis will compare OS between the two treatment arms by using a 
stratified log-rank test and the stratification factors included in the primary analysis.  The 
hazard ratio for treatment will be estimated using the stratified Cox proportional hazards 
regression model.  
Summaries showing the 1- and 2-year survival probabilities and corresponding 95% CIs 
will be provided along with graphical displays (similar to PFS).   
Objective Response Rate 
The number and proportion of subjects achieving confirmed OR (i.e. confirmed CR or 
confirmed PR) will be summarized and presented by treatment arm and cycle for the ITT 
population using a Cochran-Mantel-Haenszel (CMH) test (α=0.05) with the same 
stratification factors used for the PFS analysis.  The odds ratio and associated 95% CI 
will be calculated.  If the expected number in at least one cell is too small (<5), then 
Fisher’s exact test will be used. 
In addition, the BOR for each subject will be summarized (number and percentage of 
subjects in each category). 
Duration of Response 
Summaries and graphical displays for DoR will be similar to those of OS.  This analysis, 
however, will only apply to subjects that have achieved confirmed OR. 
4.8
Safety Evaluation 
All safety summaries and analyses will be based upon the SAF population as defined in 
Section 4.4 of this SAP. 
4.8.1
Extent of Exposure 


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Tivozanib will be administered once a day for 3 weeks, beginning on Cycle 1 Day 1 of 
each 4-week cycle.  Sorafenib will be administered twice a day continuously, also 
beginning on Cycle 1 Day 1 of each 4-week cycle. 
The following summaries will be produced by treatment arm: 
•
Number of cycles started 
•
Duration of treatment in days 
•
Total days drug was received across all cycles and for each cycle 
•
Total dose administered in mg across all cycles and for each cycle 
•
ADI, IDI, and RDI across all cycles and for each cycle  
•
Average daily dose administered in mg across all cycles and for each cycle 
•
Number and percentage of subjects on treatment by cycle  
•
Number and percentage of subjects with dose reduction, including a breakdown of 
reasons for dose reduction 
•
Number and percentage of subjects with dose interruption, including a breakdown 
of reasons for dose interruption 
Average daily dose administered is calculated as the total dose administered divided by 
the total number of days on treatment.  ADI, IDI, and RDI calculations were described in 
Section 4.6.  
A by-subject listing of exposure data will also be provided. 
4.8.2
Adverse Events 
Adverse events will be coded by system organ class (SOC) and preferred term (PT) using 
the Medical Dictionary for Regulatory Activities (MedDRA™) Version 18.0 or later.  
A TEAE is defined as an AE (identified by PT) that begins or that worsens in severity 
after at least one dose of study treatment has been administered.  Treatment-related 
TEAEs are those with reasonable causality to study drug marked as “yes” on the eCRF.  
TEAEs with an outcome of death are those with a grade of 5 or an outcome of “fatal.”  
TEAEs leading to treatment withdrawal are those with a study drug action taken of “drug 
withdrawn,” while TEAEs leading to study drug dose reduction or interruption are those 
with a study drug action taken of “dose reduced” or “drug interruption” (respectively).  
Summary tables will be presented for TEAEs by treatment arm.  An overall presentation 
of TEAE information will include the following: 
•
Number and percentage of subjects with at least one TEAE 
•
Number and percentage of subjects with at least one TEAE of Grade 3 or higher 
•
Number and percentage of subjects with at least one treatment-related TEAE  
•
Number and percentage of subjects with at least one treatment-related TEAE of 
Grade 3 or higher 
•
Number and percentage of subjects with at least one serious TEAE 


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•
Number and percentage of subjects with at least one treatment-related serious 
TEAE 
•
Number and percentage of subjects with at least one TEAE leading to death 
•
Number and percentage of subjects with at least one treatment-related TEAE 
leading to death 
•
Number and percentage of subjects with at least one TEAE leading to treatment 
withdrawal 
•
Number and percentage of subjects with at least one treatment-related TEAE 
leading to treatment withdrawal 
•
Number and percentage of subjects with at least one TEAE leading to dose 
reduction 
•
Number and percentage of subjects with at least one treatment-related TEAE 
leading to dose reduction 
•
Number and percentage of subjects with at least one TEAE leading to dose 
interruption 
•
Number and percentage of subjects with at least one treatment-related TEAE 
leading to dose interruption 
TEAE information will also be presented by NCI CTCAE severity grade and by 
relationship to study treatment.  If a subject had more than one occurrence of a TEAE, the 
most severe grade will be used in the summary tables.  
The following summaries will be provided: 
•
Number and percentage of subjects for each TEAE, categorized by SOC and PT 
•
Number and percentage of subjects for each TEAE of Grade 3 or higher, 
categorized by SOC and PT 
•
Number and percentage of subjects for each TEAE, categorized by SOC, PT, and 
maximum CTCAE grade 
•
Number and percentage of subjects for each TEAE, categorized by SOC, PT, and 
relationship to study drug 
•
Number and percentage of subjects for each treatment-related TEAE, categorized 
by SOC and PT 
•
Number and percentage of subjects for each treatment-related TEAE of Grade 3 
or higher, categorized by SOC and PT 
•
Number and percentage of subjects for each treatment-related TEAE, categorized 
by SOC, PT, and maximum CTCAE grade 
•
Number and percentage of subjects for each treatment-related TEAE leading to 
treatment withdrawal, categorized by SOC and PT 
Counts will be by subject, not by event, and subjects are only counted once within each 
SOC or PT.  For tables categorized by maximum CTCAE grade, subjects with multiple 
events within a particular SOC or PT will be counted under the category of their most 
severe event within that SOC or PT.   


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Exposure-adjusted TEAE incidence rates per 100 patient-years (p-y) may also be 
calculated by treatment arm for preferred terms of interest, as identified by AVEO.  If 
requested, the exposure-adjusted incidence rate (EAIR) per 100 p-y is the number of 
subjects who experience a TEAE divided by the total subject exposure time multiplied by 
100.  For subjects who experience a TEAE, the exposure time is from the date of first 
dose of study treatment to the time of the first occurrence of that TEAE.  For subjects 
who do not experience a TEAE, the exposure time is from the date of first dose of study 
treatment to the date of last dose of study treatment + 30 days or death date, whichever 
comes first. 
A by-subject listing of all AEs (including non-treatment-emergent events) will be 
provided.  This listing will be presented by treatment arm and will include: center, subject 
identifier, age, gender, race, adverse event (SOC, PT, and verbatim term), date of onset, 
date of resolution, duration, CTCAE grade, seriousness, action taken, outcome, and 
relatedness.  The following AE listings will also be provided using a similar layout: 
•
Subjects who died during the study 
•
Subjects with treatment-emergent SAEs 
•
Subjects with treatment withdrawal due to TEAEs 
•
Subjects with dose reduction due to TEAEs 
•
Subjects with dose interruption due to TEAEs 
For missing or partially missing dates, imputation will be done according to Section 
4.7.1.3.  In general, however, adverse events will be assumed to be treatment-emergent 
unless there is clear evidence (through comparison of partial dates) to suggest that the 
adverse event started prior to the date of first dose of study treatment or more than 30 
days after the date of last dose of study treatment.   
4.8.3
Prior and Concomitant Medications 
All medications will be collected from the time the subject signs the informed consent 
form throughout the subject’s participation in the study, including a period of 30 days 
after the subject’s last dose of study drug. 
For each concomitant medication taken during the trial, the generic component will be 
identified using the World Health Organization Drug Dictionary (WHO-DD; 
WHODDB3 ENHANCED JUN 2015).  
Medications will be assigned to a time period (prior and/or concomitant) as follows: 
•
If both the start and stop date exist and are before the first dose date of study drug, 
the medication will be counted as prior. 
•
If the start date is on or after the first dose date of study drug, the medication will 
be counted as concomitant. 


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•
If the start date is before the first dose date of study drug and the stop date is after 
the first dose date of study drug or the medication is continuing, the medication 
will be counted as prior and concomitant. 
•
If the start date is missing and the stop date is before the first dose of study drug, 
the medication will be counted as prior. 
•
If the start date is missing and the stop date is after the first dose of study drug or 
the medication is continuing, the medication will be counted as concomitant. 
•
If the start and stop dates are missing, the medication will be counted as 
concomitant. 
Summaries showing number of subjects and percentage taking each medication will be 
provided for each preferred medication term by treatment arm.  This will be done 
separately for prior and for concomitant medications. 
A by-subject listing of all prior and concomitant medication data will also be provided. 
4.8.4
Clinical Laboratory Evaluation 
Local laboratories will be used for laboratory safety evaluations in this study.  For a list 
of the parameters to be evaluated, see Section 3.2.2 of this SAP.  Laboratory normal 
ranges will be provided by the local laboratory.  For parameters where an NCI CTCAE 
v.4.03 scale exists, laboratory results will be graded according to the NCI CTCAE v.4.03 
severity grade.  For parameters for where an NCI CTCAE v.4.03 scale does not exist, an 
indicator of whether the value is below, within, or above the normal range will represent 
severity instead.   
All laboratory values will be reported in SI units.    
Summaries for each laboratory parameter will be presented by treatment arm and visit.        
For by-visit summaries, the first non-missing assessment (including repeat assessments) 
recorded at each visit will be used. Optional laboratory parameters will not be 
summarized by treatment arm, only listed. 
For laboratory values reported as a character value, such as <40, will be transformed into 
numerical values for summary reasons by following the specified guidelines.  If a 
laboratory value is reported using the less than symbol, ‘<’, 0.10 will be subtracted from 
the original numeric value.  If a laboratory value is reported using the greater than 
symbol, ‘>’, 0.10 will be added to the original numeric value. 
Observed and change from baseline values in laboratory test results will be analyzed 
using descriptive statistics (except for parameters with categorical results, which will use 
frequencies and percentages).  Change from baseline will only apply to post-baseline 
assessments for parameters with continuous results.  For each lab parameter at each time 
point, the difference in mean changes from baseline (tivozanib – sorafenib) using a rank-


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sum test will be presented along with the 95% CI.  Laboratory results will also be 
summarized by maximum CTC grade or by worst severity, depending on the parameter.  
Shifts in grade from baseline to each post-baseline visit will be summarized by treatment 
arm.   The maximum shift (across all visits) from baseline will also be summarized by 
treatment arm.  If needed, significance of shifts in laboratory parameters may be further 
evaluated within each treatment arm using a generalized McNemar’s test. 
A by-subject listing of all laboratory data, with abnormal values flagged, will be provided 
by treatment arm.  This listing will include center, patient identifier, age, gender, race, 
weight, and visit, as well as laboratory reference ranges for each parameter.  A similar 
listing with out-of-reference range values will also be presented.  
4.8.5
Vital Signs, Physical Findings and Other Observations Related to Safety 
A description of vital sign parameters, ECG results, ECOG performance status, and 
physical examination can be found in Section 3.2.2 of this SAP. 
Summaries for each vital sign parameter will be presented by treatment arm and visit.      
Observed and change from baseline values in vital sign results will be analyzed using 
descriptive statistics.  Change from baseline will only apply to post-baseline assessments.  
For each vital sign parameter at each time point, the difference in mean changes from 
baseline (tivozanib – sorafenib) using a rank-sum test will be presented along with the 
95% CI. 
Shifts in ECG results, ECOG performance status, and physical examination from baseline 
to each post-baseline visit (where available) will be summarized by treatment arm.  The 
maximum shift (across all visits) in ECG results and ECOG performance status from 
baseline will also be summarized by treatment arm. 
For systolic blood pressure (SBP) and diastolic blood pressure (DBP), observed values 
will be classified as markedly abnormal (MA) or not markedly abnormal (NMA).  The 
criteria for determining MA values are as follows: 
•
SBP <=80 mmHg or >=180 mmHg 
•
DBP <=50 mmHg or >=105 mmHg 
The number and percentage of subjects with MA change values will be summarized for 
each vital sign parameter by treatment arm and visit. 
By-subject listings of vital sign data, ECG results, ECOG performance status, and 
physical examination results will be provided by treatment arm. 
4.8.6
Safety Monitoring Committee  
The objectives of the Safety Monitoring Committee (SMC) are to evaluate interim safety 
data to protect subject welfare and to identify issues and risks, as well as to provide 


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recommendations regarding study design and conduct. The SMC is composed of six 
members, all of whom are qualified clinicians in general oncology and renal cell 
carcinoma and have practical experience conducting and monitoring the safety and 
efficacy of clinical trials. 
A meeting to review cumulative safety data will be planned after the first 50 subjects are 
randomized to each treatment arm and approximately every 6 months thereafter.  There 
may be additional ad hoc meetings (via teleconference or face-to-face) to evaluate the 
safety of the subjects, when internal reviews detect safety risks. The frequency may be 
modified at the discretion of the SMC 
After each meeting, the SMC will make recommendations to modify or terminate the trial 
if there is a safety concern or a significant emerging issue with trial design or conduct.  
Further details on the Safety Monitoring Committee activities can be found in the SMC 
Charter. 
4.9
Determination of Sample Size 
A sample size of 322 subjects (161 subjects per treatment arm) with a total number of 
255 events will provide 90% power to detect a statistically significant difference between 
treatment arms with respect to PFS as assessed by the IRR. The sample size was 
determined based on the following assumptions:  
•
The distribution of the PFS for the two treatment arms will be compared by using 
a log-rank test with one-sided 2.5% significance level.  
•
The median PFS for subjects receiving sorafenib and tivozanib is 4 months and 6 
months, respectively (an increase of 2 months or 50%). 
•
An equal number of subjects will be assigned to each treatment arm. 
•
Enrollment will take 15 months.  
•
The drop out percentage per treatment arm will be 3%. 
The first secondary analysis will compare OS between sorafenib and tivozanib by using a 
stratified log-rank test (stratification factors included in the primary analysis), and two-
sided 0.8% significance level (utilizing a Lan-DeMets alpha spending function with an 
O’Brien Fleming boundary).  The interim OS analysis will be done at the time of the final 
PFS analysis.  Assuming a median OS for sorafenib of 12 months and a median OS for 
tivozanib of 16 months, 245 OS events at the time of final OS analysis and 149 OS events 
at the time of final PFS analysis will yield approximately 61% power to demonstrate 
longer OS for tivozanib using the log-rank test, given 2.5% type I error (one-sided).  The 
final OS analysis will be performed when all subjects have been lost to follow-up, have 
withdrawn consent, have died, or when all subjects in follow-up have been on-study for 
at least 2 years, whichever occurs first. 
The estimate was obtained by using East® statistical package Version 6.3 by Cytel Inc. 


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4.10 Changes in the Conduct of the Study or Planned Analysis 
Protocol Version 4.0 was finalized on 01 October 2018.  The administrative change was: 
•
A previously unspecified data cut-off date for the primary analysis was 
established to be 04 October 2018 with a targeted number of 242 PFS events. 
The PFS event rate continues to decelerate. The study steering committee participated in 
a conference call on Thursday, August 30, 2018 and unanimously recommended 
performing the analysis rather than waiting for the additional events to reach the planned 
255 PFS events.  The reasons given were that the current patients have been on study for 
at least one year and may not progress for some time, and that the small reduction in 
events at the time of final analysis was unlikely to materially affect the results.   
•
The committee was concerned that based on the small number of patients 
remaining that can contribute to a PFS event, it could take another 5 months or 
more to get to 255 events.  
•
Some committee members expressed that based on the safety profiles they have 
observed during the study, they are keen to provide access to this drug to their 
patients. 
This proposal was presented to the US FDA and they reported the decision is at the 
discretion of the Steering Committee and the sponsor. 
Protocol Version 3.0 was finalized on 13 July 2016.  Changes that have statistical 
implications are: 
•
the removal of the tertiary objective of exploring the correlation of serum-
neuropilin 1 (NPR-1) with clinical activity in subjects randomized to treatment 
with tivozanib or sorafenib. 
•
The addition of the tertiary objectives of exploring the relationship between 
tivozanib and sorafenib drug levels and activity as well as the relationship 
between the IP drug levels and AEs. 
Subjects must begin planned treatment of the study drug within 14 days after 
randomization. 
An exploratory analysis of PFS on the safety population was added to the SAP to account 
for subjects that were randomized to a treatment arm but not dosed due to external issues. 
Best Overall Response criteria was updated to align with the RECIST 1.1 guidelines. 
5
REFERENCES 
[1] International Conference on Harmonisation (ICH) of Technical Requirements for 
Registration of Pharmaceuticals for Human Use: ICH Harmonised Tripartite 


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Guideline Statistical Principles for Clinical Trials E9. (1998). http://www.ich.org/ 
fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E9/Step4/ 
E9_Guideline.pdf 
[2] New response evaluation criteria in solid tumours:  Revised RECIST guideline 
(version 1.1). (2009). http://www.eortc.be/Recist/documents/RECISTGuidelines.pdf 


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