Clinical trial NCT01835223
Conditions: Advanced Adult Hepatocellular Carcinoma Non-Resectable Hepatocellular Carcinoma
Sponsor: Roswell Park Cancer Institute
Start date: 2013-07-11; Completion date: 2019-11-08
Enrollment: 33 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This phase I/II trial studies the side effects and best dose of tivozanib and to see how well it works in treating patients with liver cancer that has spread to other parts of the body or cannot be removed by surgery. Tivozanib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Detailed description:
PRIMARY OBJECTIVES:

I. Progression free survival (PFS) at 24 weeks in patients with advanced hepatocellular carcinoma (HCC).

SECONDARY OBJECTIVES:

I. To determine the safety of tivozanib in HCC. II. To determine the overall survival (OS) and clinical benefit rate (complete response \[CR\], partial response \[PR\] and stable disease \[SD\]) by Response Evaluation Criteria in Solid Tumors (RECIST).

III. To determine the steady state pharmacokinetics (PK) and soluble vascular endothelial growth factor receptor 2 (VEGFR-2) baseline/change with tivozanib and use modeling to correlate exposure with biomarker change and the primary outcome measure of PFS.

IV. To determine the change in viral load (hepatitis B virus \[HBV\] and hepatitis C virus \[HCV\]) during therapy in patients with HBV or HCV associated HCC.

V. To determine the change in tumor marker (alfa fetoprotein) with tivozanib therapy is in the effect of tivozanib on several tumor-associated immune response markers.

OUTLINE: This is a phase I, dose-escalation study followed by a phase II study.

Patients receive tivozanib orally (PO) once daily (QD) on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 6 months.

Arms: arm 1: Patients receive tivozanib PO QD on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. arm 2: Patients receive tivozanib PO QD on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: Tivozanib (1mg) intervention 2: Tivozanib (1.5mg)
Intervention descriptions: intervention 1: Given PO intervention 2: Given PO

Protocol documents:
Prot_SAP_000.pdf: 
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Multicenter Phase 1b/2 Study of Tivozanib in Patients with Advanced Inoperable 
Hepatocellular Carcinoma
Roswell Park Cancer Institute
Study Number:
I 229112
Initial Date:
November 9, 2012
Amendment #1
Amendment #2
Amendment #3
Amendment #4
Amendment #5
Amendment #6
Amendment #7
Amendment #8
Amendment #9
Amendment #10
Amendment #11
Amendment #12
04.04.13
05.28.13
08.27.13
12.04.13
03.10.14
04.07.14
07.09.14
09.18.14
08.05.15
10.13.15
10.12.16
12.22.16
IND Number/Holder:
IND 118593  
Principal Investigator:
Renuka Iyer, MD
Roswell Park Cancer Institute
Elm and Carlton Streets
Buffalo, New York 14263
716-845-3099
Renuka.Iyer@RoswellPark.org
Funding Organization::
NCCN
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Industry/Other Supporter:
AVEO Pharmaceuticals  
Confidentiality Statement
Any and all information presented in this document shall be treated as confidential and shall 
remain the exclusive property of the party (ies) mentioned above. The use of such confidential 
information must be restricted to the recipient for the agreed purpose and must not be disclosed, 
published, or otherwise communicated to any unauthorized persons, for any reason, in any form 
whatsoever without the prior written consent of the party(ies) above.
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RPCI Study Contacts 
FOR NETWORK SITES: Please contact the RPCI Network Monitor for any study-related 
questions regarding sample handling, processing or shipping.
Study personnel outside of RPCI-CRS who will be housing essential study documents or 
receiving, analyzing or storing biological samples. This contact list is to include all internal 
and external laboratories and their primary laboratory contacts. NOTE: Personnel from 
any potential network site are NOT to be included on this contact page.
Name
Institution
Email
Role
Bioanalytics, 
Metabolomics & 
Pharmacokinetics Core 
Facility
716-845-3303 
Roswell Park Cancer 
Institute, Buffalo, NY
PKPDCore@RoswellPark.org
PK/PD analysis
Yasmin Thanavala, 
PhD
Laboratory: 
716-845-8536
716-845-8535
716-845-4592
Roswell Park Cancer 
Institute, Buffalo, NY
Yasmin.Thanavala@RoswellPark.org.
Immune biomarker 
analysis
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SYNOPSIS
Title / Phase
Multicenter Phase 1b/2 Study of Tivozanib in Patients with Advanced 
Inoperable Hepatocellular Carcinoma
Roswell Park Cancer Institute 
Study Number
I 229112
Roswell Park Cancer Institute 
Investigator
Renuka Iyer, MD
Sponsor
Roswell Park Cancer Institute
Study Drug
Tivozanib
Objectives
Primary Objective:
•
The primary endpoint of the study is PFS at 24 weeks in patients with 
advanced HCC. Patients who remain alive without evidence of disease 
progression (per RECIST) for at least 24 weeks after enrollment will be 
considered PFS responders.
Secondary Objectives:
•
To determine the safety of tivozanib in HCC.
•
To determine the OS and clinical benefit rate (CR, PR and SD) by RECIST.
•
To determine the steady state PK and soluble VEGFR-2 baseline/ change 
with tivozanib and use modeling to correlate exposure with biomarker 
change and the primary outcome measure of PFS.
•
To determine the change in viral load (HBV and HCV) during therapy in 
patients with HBV or HCV associated HCC.
•
To determine the change in tumor marker (alfa fetoprotein) with tivozanib 
therapy is in the effect of tivozanib on several tumor-associated immune 
response markers.
Study Design
Multicenter Phase 1b/2 study of tivozanib in patients with advanced inoperable 
hepatocellular carcinoma.  The Phase 2 portion includes early stopping rules for 
futility.
Target Accrual and Study 
Duration
Between 6 and 18 patients will be enrolled in Phase 1b portion of this study. Six 
Phase 1b patients treated at the recommended Phase 2 dose will be included in 
the Phase 2 portion of this study. An additional 31 patients will be enrolled for 
the Phase 2 portion, for a total Phase 2 sample size of 37. This study is expected 
to accrue 9 patients to the Phase 1b, for a combined sample of size of 40 (9+37-
6). If 18 patients are enrolled in the Phase 1b, the maximum combined sample 
size will be 49 (18+37-6).
The number of subjects required is a function of the unknown PFS response 
rate. Accrual is expected to take up to 4 years. The duration the patients will be 
on study will be approximately 2 years.
Study Procedures
Physical Examination
Hematology
Chemistry
PT/INR
UPCR 
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Alpha-Fetoprotein (AFP) 
HBsAg; HCV Ab; (if unknown)
Viral Load (if either or both HBsAg or HCV Ab are positive)
PK/PD sVEGF-2 Sampling
Immune Biomarker Sampling
ECOG Performance Status
Electrocardiogram
CT Scan (within 4 weeks)
Adverse Events
Statistical Analysis
Sample Size Determination:  Sample size for the Phase 1 portion depends on 
the unknown dose-toxicity profile. For the Phase 2 portion, with 
= 0.05, 

assessment of 37 patients gives 80% power to detect minimum 20 percentage 
point improvement in the 24 week PFS response rate, assuming a 50% rate 
under the standard of care.
Randomization: No randomization is required.
Efficacy Analysis: Primary interest is in the PFS response rate 24 weeks after 
enrollment. The response rate will be described by binomial proportion 
estimates and 95% confidence intervals. All enrolled patients will be included in 
this primary analysis.
Safety Analysis: Adverse events will be tabulated. AE rates will be described 
using binomial proportions and 95% confidence intervals.


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Subject Name: (Network Sites use Initials) ________________________________________
Medical Record No.: (Network Sites use Subject ID#)________________________________
Title: Multicenter Phase 1b/ 2 Study of Tivozanib in Patients with Advanced Inoperable 
Hepatocellular Carcinoma
INCLUSION CRITERIA
Yes
No
N/A
All answers must be “YES” or “N/A” for subject enrollment.
DATE
1.
Advanced staged HCC (unresectable and not amenable to local or regional 
therapy; or metastatic HCC). The diagnosis of HCC should be based on at 
least one of the following:
a)
MRI or CT consistent with liver cirrhosis AND at least one solid liver 
lesion measuring ≥ 2 cm, with characteristics arterial enhancement and 
venous washout regardless of AFP levels.
b)
AFP ≥ 400 ng/mL AND evidence of at least one solid liver lesion 
≥ 2 cm regardless of specific imaging characteristics on CT or MRI.
c)
Histological/cytology biopsy confirming HCC.
2.
Patients must have measurable disease per RECIST 1.1 criteria, defined as 
at least 1 lesion that can be accurately measured in at least one dimension, 
and that has not been the target of local or regional therapy including 
transarterial chemoembolization, intra-arterial chemotherapy, ethanol, or 
radiofrequency ablation.
3.
Age ≥ 18 years.
4.
Life expectancy of greater than 3 months.
5.
Patients must have organ and marrow function as defined below:
•
Child-Pugh liver function Class A.
•
AST ≤ 5 x Institutional upper limits of normal (ULN)
•
Total bilirubin ≤ 3 mg/dL
•
INR ≤ 2.0 (unless due to therapeutic warfarin use)
•
Serum albumin > 2.8 g/dL
•
Creatinine ≤ 1.5 x Institutional ULN
•
ANC > 1200/mm3
•
Platelets ≥ 60,000/mm3
•
Hgb ≥ 8.5 g/dL
NOTE: The lower absolute neutrophil count (ANC) and platelet cut-offs are 
designed to accommodate the large number of patients with HCC who have 
portal hypertension and splenic sequestration. Given the adverse profile of 
tivozanib these reduced cut-offs are thought to be safe.
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Subject Name: (Network Sites use Initials) ________________________________________
Medical Record No.: (Network Sites use Subject ID#)________________________________
Title: Multicenter Phase 1b/ 2 Study of Tivozanib in Patients with Advanced Inoperable 
Hepatocellular Carcinoma
INCLUSION CRITERIA
Yes
No
N/A
All answers must be “YES” or “N/A” for subject enrollment.
DATE
6.
Patients must not have any evidence of bleeding diathesis or active 
gastrointestinal bleeding. 
7.
Patients must not be known to be HIV positive; drug-drug interaction with 
study medication and HIV medications is not well-characterized and could 
lead to unwanted side effects.
8.
Patients must not have other uncontrolled intercurrent illnesses (excluding 
HBV or HCV). This includes (but is not limited to) ongoing or active 
infection, symptomatic congestive heart failure, unstable angina pectoris, 
cardiac arrhythmia, or psychiatric illness/social situations that would limit 
compliance with study requirements.
9.
Sexually active fertile patients (male and female), and their partners, must 
agree to use medically accepted methods of contraception during the 
course of the study and for 3 months after the last dose of the study drug.
10. Female patients of childbearing potential must have a negative pregnancy 
test at screening.
11. Have an ECOG Performance Status of ≤ 2. Refer to Appendix B.
12. Subject or legal representative must understand the investigational nature 
of this study and sign an Independent Ethics Committee/Institutional 
Review Board approved written informed consent form prior to receiving 
any study related procedure.
Investigator Signature: ___________________________________
Date: ____________
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Subject Name: (Network Sites use Subject Initials) __________________________________
Medical Record No.: (Network Sites use Subject ID#) _______________________________
Title: Multicenter Phase 1b/2 Study of Tivozanib in Patients with Advanced Inoperable 
Hepatocellular Carcinoma
EXCLUSION CRITERIA
Yes
No
N/A
All answers must be “NO” or “N/A” for subject enrollment
DATE
1.
Patients who have had prior anti-angiogenic therapy, including but not 
limited to sorafenib, brivanib, bevacizumab, or sunitinib.
2.
Patients who have had any prior line of systemic therapy including 
cytotoxic agents or molecularly targeted agents for 
advanced/unresectable disease. Any number of prior regional therapies 
with transarterial chemoembolization (TACE), brachytherapy with 
Yttrium-90 microsphere, intra-arterial chemotherapy, surgery, or 
ablative therapy is allowed.
3.
Prior liver transplantation and on immunosuppression; drug-drug 
interaction with study medication and immunosuppression is not well-
characterized and could lead to unwanted side effects.
4.
Known symptomatic or uncontrolled brain metastases or epidural 
disease.
5.
Patient has a corrected QT interval (QTcF) > 500 ms at screening.
6.
The patient is unable to swallow pills or diagnosed with a 
gastrointestinal disorder that are likely to interfere with the absorption 
of the study drug or with the patient’s ability to take regular oral 
medication.
7.
The patient is pregnant or breastfeeding.
8.
Patients with second primary cancer (except adequately treated 
nonmelanoma skin cancer, curatively treated in-situ carcinoma of the 
cervix or superficial bladder cancer, or other solid tumors including 
lymphoma without bone marrow involvement curatively treated with no 
evidence of disease for ≥ 5 years).
9.
The patient has a previously-identified allergy or hypersensitivity to 
components of the study treatment formulation.
10. Patients receiving any medications or substances that are strong 
inducers of CYP3A4 are ineligible. Moderate and mild inducers of 
CYP3A4 should be used with caution as they reduce the efficacy of 
Tivozanib.
11.  Urine protein: creatinine ratio > 1 (see Appendix- H)
Study participant meets all entry criteria:
Yes
No
Investigator Signature: ___________________________________
Date: ____________
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TABLE OF CONTENTS
1
Background ............................................................................................................................13
1.1
Study Disease – Hepatocellular Carcinoma .......................................................................13
1.2
Study Drug - Tivozanib Hydrochloride..............................................................................14
1.3
Preclinical Studies with Tivozanib .....................................................................................14
1.4
Clinical Studies with Tivozanib..........................................................................................14
1.5
Tivozanib Hydrochloride Safety Experience......................................................................15
1.6
Correlative Studies..............................................................................................................17
1.6.1
Pharmacokinetic/ Pharmacokinetic and VEGFR-2.........................................................17
1.6.2
Immune Biomarker .........................................................................................................17
1.7
Risks and/or Benefits..........................................................................................................18
2
Rationale.................................................................................................................................18
3
Objectives...............................................................................................................................19
3.1
Primary Objective...............................................................................................................19
3.2
Secondary Objectives .........................................................................................................19
3.3
Study Design.......................................................................................................................19
3.3.1
Phase 1b ..........................................................................................................................19
3.3.2
Phase 2 ............................................................................................................................20
3.3.3
Treatment Cycle..............................................................................................................20
3.4
Target Accrual and Study Duration....................................................................................20
4
Subject Selection ....................................................................................................................21
4.1
Inclusion Criteria ................................................................................................................21
4.2
Exclusion Criteria ...............................................................................................................22
4.3
Inclusion of Women and Minorities...................................................................................23
5
Investigational Product...........................................................................................................23
5.1
Active Substance and Source..............................................................................................23
5.2
Drug Shipment....................................................................................................................23
5.3
Storage and Stability...........................................................................................................23
5.4
Handling and Disposal........................................................................................................23
6
Treatment Plan .......................................................................................................................24
6.1
Preparation and Administration..........................................................................................24
6.2
Dose Modifications.............................................................................................................25
6.2.1
Definition of Dose-Limiting Toxicity.............................................................................25
6.2.2
Treatment Delay..............................................................................................................26
6.2.3
Tivozanib Hydrochloride Dose Interruption...................................................................26
6.2.4
Tivozanib Hydrochloride Dose Reduction .....................................................................26
6.2.5
Management of Hypertension.........................................................................................27
6.3
General Concomitant Medication and Supportive Care.....................................................27
6.4
Treatment Discontinuation .................................................................................................27
6.5
Compliance.........................................................................................................................28
7
Study Procedures....................................................................................................................28
7.1
Baseline Evaluations...........................................................................................................28
7.2
Evaluations Performed at Cycle 1, Day 1...........................................................................29
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7.3
Evaluations Performed at Cycle 1, Day 15 (± 3 Days).......................................................30
7.4
Evaluations Performed at Day 1 of Each Cycle After Cycle 1 (± 3 Days).........................30
7.5
Evaluations Performed at Cycle 3, Day 1 (± 3 Days).........................................................31
7.6
Evaluations Performed at 1 Year (± 7 Days)......................................................................31
7.7
Evaluations Performed at End of Treatment ......................................................................31
7.8
Follow-Up: Medical Record review every 6 months for overall survival..........................32
7.9
Schedule of Procedures and Observations..........................................................................32
7.10
Pharmacokinetic/Pharmacodynamic Blood Sample Collection and Processing................35
7.11
Immune Biomarker Blood Sample Collection and Processing ..........................................36
8
Efficacy Evaluations...............................................................................................................37
8.1
Objective Tumor Response.................................................................................................37
8.2
Target Lesions ....................................................................................................................37
8.3
Non-Target Lesions ............................................................................................................38
8.4
Evaluation of Response ......................................................................................................38
8.5
Confirmation Measurement................................................................................................40
8.6
Guidelines for Evaluation of Measurable Disease..............................................................40
9
Safety Evaluation ...................................................................................................................42
9.1
Adverse Events ...................................................................................................................42
9.1.1
Definition ........................................................................................................................42
9.1.1.1
Diagnosis Versus Signs and Symptoms ......................................................................42
9.1.1.2
Adverse Events Occurring Secondary to Other Events...............................................42
9.1.1.3
Abnormal Laboratory Values......................................................................................43
9.1.1.4
Preexisting Medical Conditions (Baseline Signs and Symptoms) ..............................43
9.1.2
Grading and Relationship to Drug ..................................................................................43
9.1.3
Reporting Adverse Events (Network Sites see Appendix A ) ........................................44
9.2
Serious Adverse Events ......................................................................................................45
9.2.1
Definition ........................................................................................................................45
9.2.2
Reporting Serious Adverse Events (Network Sites see Appendix A ) ...........................45
9.2.3
Follow-Up for Serious Adverse Events ..........................................................................45
9.3
Unanticipated Problems......................................................................................................46
9.3.1
Definition ........................................................................................................................46
9.3.2
Reporting Unanticipated Problems .................................................................................46
9.4
Investigator Reporting: Notifying the Study Sponsor ........................................................46
9.5
FDA Reporting ...................................................................................................................47
9.6
Procedures for Reporting Subject Death ............................................................................48
9.7
Procedures for Reporting Study Drug Overdose................................................................48
9.8
Procedures for Reporting Drug Exposure During Pregnancy and Birth Events ................48
10
Data and Safety Monitoring................................................................................................49
11
Statistical Methodology......................................................................................................49
11.1
Phase 1b..............................................................................................................................49
11.2
Phase 2................................................................................................................................50
11.3
Sample Size Determination ................................................................................................50
11.4
Randomization....................................................................................................................50
11.5
Demographics and Baseline Characteristics.......................................................................51
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11.6
Efficacy Analysis................................................................................................................51
11.7
Safety Analysis ...................................................................................................................51
11.8
Interim Analysis and Criteria for Early Termination of the Study.....................................51
12
Correlative Data Analysis...................................................................................................52
12.1
Pharmacokinetic/Pharmacodynamic Analysis....................................................................52
12.2
Immune Biomarker.............................................................................................................53
13
Ethical and Regulatory Standards.......................................................................................54
13.1
Ethical Principles................................................................................................................54
13.2
Informed Consent ...............................................................................................................54
14
Study Responsibilities ........................................................................................................55
14.1
Data Collection ...................................................................................................................55
14.2
Maintenance of Study Documents......................................................................................55
15
Administrative Rules ..........................................................................................................55
15.1
Revisions to the Protocol....................................................................................................55
15.2
Termination of the Study....................................................................................................56
15.3
Confidentiality ....................................................................................................................56
15.4
Compliance with Laws and Regulations ............................................................................56
15.5
Record Retention ................................................................................................................56
15.6
Publication Statement .........................................................................................................56
16
Appendices .........................................................................................................................57
17
References...........................................................................................................................70
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IN-TEXT TABLES
Table 1.
Adverse Events Expected to Occur with Tivozanib Hydrochloride Monotherapy.....16
Table 2.
Dose Schedule .............................................................................................................25
Table 3.
Tivozanib Hydrochloride Dose Modification Guidelines for Drug-Related
Adverse Events ............................................................................................................26
Table 4.
Schedule of Procedures and Observations ..................................................................33
Table 5.
Time Point Response Criteria (+/- non-target disease) ...............................................39
Table 6.
Time Point Response Criteria (non-target disease only).............................................39
Table 7.
Guidelines for Routine Adverse Event Reporting for Phase 1 Studies
(Regardless of Expectedness)......................................................................................44
Table 8.
Guidelines for Routine Adverse Event Reporting for Phase 2 Studies
(Regardless of Expectedness)......................................................................................44
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APPENDICES
Appendix A.
Network Sites.......................................................................................................58
Appendix B.
ECOG Performance Status Scores.......................................................................61
Appendix C.
Recommended Management for Tivozanib Hydrochloride-Related
Hypertension ........................................................................................................62
Appendix D.
Recommended Anti-Hypertensive Medications ..................................................63
Appendix E.
Patient Pill Diary..................................................................................................64
Appendix F.
Separation of PBMC on FICOLL Hypaque Gradient..........................................65
Appendix G.
Child-Pugh liver function Class A.......................................................................68
Appendix H.
Procedure for Obtaining a Urine Protein /Creatinine Ratio.................................69
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1
BACKGROUND
Primary HCC is the sixth most common malignancy diagnosed worldwide. HCC results in 
between 250,000 and one million deaths globally per year and its incidence continues to increase 
in the developed world. HCC is an aggressive tumor that often occurs in the setting of chronic 
liver disease and cirrhosis and is often diagnosed late in its course, as there are no biomarkers to 
detect it when it is incipient and potentially curable. Median survival following diagnosis is less 
than 6 months. Treatment options are divided into surgical therapies (i.e., resection, cryoablation, 
and orthotopic liver transplantation [OLT]), and nonsurgical therapies (i.e., percutaneous ethanol 
injection (PEI), radiofrequency ablation (RFA), transarterial chemoembolization (TACE), 
systemic chemotherapy, and radiation). Curative therapies such as resection, transplantation, or 
percutaneous therapies benefit only 25% of patients. Majority of patients are not eligible for such 
therapies because of tumor extent or underlying liver dysfunction. Improving treatment outcomes 
in patients with advanced stage hepatocellular carcinoma (HCC) requires the development of 
agents with tolerable safety profiles and the identification of biomarkers capable of predicting 
tumor response or resistance to treatment. The underlying etiology for HCC development is often 
chronic viral infection and inflammation due to hepatitis and cirrhosis affects both tumor 
progression and immune cell networks.1
1.1
Study Disease – Hepatocellular Carcinoma
Liver cancer is a common and rapidly fatal malignancy, with the third highest cancer mortality in 
2008. Hepatocellular carcinoma (HCC) is the most common type of liver cancer, accounting for 
about 80% of all cases of cancers originating in the liver. HCC is a hypervascular malignancy 
and VEGF is frequently expressed and associated with poor prognosis.2 VEGF induces 
endothelial cell proliferation and vascular permeability and its effects are mediated through 
multiple receptors, including VEGFR-2.3 VEGFR-2 is the predominant mediator of 
VEGF-stimulated endothelial cell migration, proliferation, survival, and enhanced vascular 
permeability. High VEGF HCC tumor expression has been correlated with vascular invasion and 
poor patient survival. VEGFR-2 has been shown to be more strongly expressed in HCC 
compared to dysplastic nodules and background cirrhotic liver, and VEGFR-2 up-regulation is a 
feature of poor differentiation and tumor progression. Therefore, VEGFR-2 is an important 
regulator of VEGF-induced tumor development and angiogenesis. Systemic therapy using 
targeted therapy for advanced-stage HCC appeared promising in Phase 2 studies delaying 
progression free survival despite no radiographic shrinkage in the tumor and led to confirmatory 
Phase 3 studies that led to FDA approval of the multikinase inhibitor, sorafenib. Sorafenib 
targets Raf kinase and receptor tyrosine kinase activity of platelet-derived growth factor receptor 
β (PDGFR-β) and vascular endothelial growth factor receptors (VEGFRs) 1, 2 and 3.31, 32 
Since its approval in 2008, no other targeted therapies have shown superior activity or safety 
profiles in the treatment of advanced HCC.4
Although sorafenib has been approved for use, in clinical practice the drug has many toxicities 
and overall survival even in western populations with good supportive care remains only 
10.7 months, 2 months greater than placebo. In addition, the primary endpoint of improved 
symptom control was not achieved and 66% of patients either need dose reductions or delays and 
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discontinue drug for reasons other than disease progression that speak also to the limited 
tolerability of this drug and also the challenges with developing safe and efficacious therapies for 
this disease population. Despite these limitations with the approval of sorafenib targeting 
angiogenesis is and will remain the backbone for HCC therapy for the foreseeable future.5 Novel 
agents that target this pathway and have sound preclinical rationale need to be evaluated to 
improve outcomes for patients with this disease. In addition, there is a need to incorporate and 
prospectively validate novel biomarkers that will predict response to such therapies.
1.2
Study Drug - Tivozanib Hydrochloride
Tivozanib hydrochloride (also known as AV-951; previously known 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 hydrochloride is a novel and potent 
pan-vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitor with potent 
activity against all 3 VEGF receptors (VEGFR-1, VEGFR-2, and VEGFR-3).6 Tivozanib 
hydrochloride inhibits phosphorylation of VEGFR-1, VEGFR-2 and VEGFR-3 at picomolar 
concentrations (IC50 of 0.21, 0.16 and 0.24 nM, respectively), and inhibits c-Kit and PDGFR at 
10-times higher concentrations (IC50 of 1.63 and 1.72 nM, respectively). In nonclinical models 
and studies performed in humans, tivozanib hydrochloride has shown strong anti-angiogenesis 
and antitumor activity. VEGF is a potent induction factor, playing a central role in angiogenesis 
and vascular permeability of tumor tissues. By inhibiting VEGF-induced VEGFR activation, 
tivozanib hydrochloride inhibits angiogenesis and vascular permeability in tumor tissues, leading 
indirectly to inhibition of tumor growth.7
Tivozanib hydrochloride has been studied in several clinical trials in multiple tumor types. A 
summary of tivozanib’s hydrochloride pertinent efficacy results and safety data follow. Please 
refer to the tivozanib hydrochloride Investigator Brochure (IB) for descriptions of all available 
data.
1.3
Preclinical Studies with Tivozanib
A detailed discussion of the preclinical pharmacology, pharmacokinetics, and toxicology of 
tivozanib can be found in the Investigator’s Brochure.
1.4
Clinical Studies with Tivozanib
Clinical activity data are available for 3 monotherapy studies and for 2 combination therapy 
studies. Clinical response was assessed using RECIST (Response Evaluation Criteria in Solid 
Tumors, Version 1.1).
Forty-one patients with advanced solid tumors received tivozanib hydrochloride monotherapy 
given orally for 28-consecutive days followed by a 14-day rest period in a Phase 1 study 
(KRN951/03-B01). The maximum tolerated dose (MTD) of tivozanib hydrochloride was 
determined to be 1.5 mg/day. Overall, 46.3% of subjects experienced some level of disease 
control. Most subjects had a best overall response of stable disease [SD] (43.9%) or progressive 
disease [PD] (43.9%). The median time to disease progression across all treatment groups was 
3.9 months (95% CI: 2.7, 6).
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In a Phase 2 study (AV-951-07-201) in 272 patients with metastatic renal cell carcinoma (RCC), 
there were 2 primary efficacy analyses: best tumor response rates throughout the 16-week 
open-label period and progression-free survival (PFS) rates at 12 weeks post-randomization. 
Throughout the 16-week, open-label period, the overall response rate (ORR) for all treated 
subjects was 24.6% by investigator assessment and 18% by independent radiology review (IRR) 
assessment. By both investigator assessment and IRR assessment, the disease control rate (DCR) 
for all treated subjects was 84.2% (229/272 subjects). At 12 weeks post-randomization, PFS rates 
were 57.4% for tivozanib hydrochloride subjects and 28.1% for placebo subjects (p = 0.001). By 
IRR assessment, PFS rates were 49.2% for tivozanib hydrochloride subjects and 21.1% for 
placebo subjects (p = 0.001).
Sixteen subjects with non-small cell lung cancer (NSCLC) were treated with tivozanib 
hydrochloride in a Phase 1 continuous-dosing monotherapy study. No subject had a confirmed 
best overall response of complete response (CR) or partial response (PR). Four subjects had SD. 
Duration of SD, for the 4 subjects with confirmed SD, ranged from 7 weeks to 32 weeks. Disease 
control was confirmed in 25% of subjects. Time to progression (TTP) was less than 10 weeks for 
most subjects.
Tivozanib hydrochloride was combined with temsirolimus in a Phase 1b study in patients with 
metastatic RCC. Of the 22 subjects evaluable for a secondary endpoint of efficacy, no subject 
had confirmed CR, 5 subjects had confirmed PR, and 15 subjects had confirmed SD. Reported 
ORR and DCR were 22.7% and 90.9%, respectively.
In a Phase 1b study of tivozanib hydrochloride combined with paclitaxel in a cohort of invasive 
breast cancer patients, ORR, DCR, and TTP were among the secondary efficacy variables. 
Thirteen subjects were included in the efficacy evaluable population. No subject had a confirmed 
CR, 4 subjects had confirmed PR, 6 subjects had SD, and 1 subject had PD. For responses 
confirmed by RECIST, ORR was 30.8% and DCR was 76.9%. In the 4 subjects demonstrating a 
PR, the duration ranged from 5.6 to 9.4+ months and TTP ranged from 9.7 to 13.1+ months.
1.5
Tivozanib Hydrochloride Safety Experience
Clinical data are available for 14 completed or ongoing clinical studies of tivozanib 
hydrochloride. Adverse events were generally manageable using standard medical therapy and/or 
discontinuation or reduction of study drug.
Related treatment emergent adverse events (TEAEs) that resulted in a fatal outcome occurred in 
4 subjects and included post-procedural hemorrhage, cerebrovascular accident, pulmonary 
embolism, and hypertension.
Related TEAEs for combination therapy studies can be summarized as follows:
•
Combination Therapy Studies: Related TEAEs were reported in 65/81 subjects (80.2%). 
The most frequently related TEAEs (occurring in ≥ 10% of treated subjects) were fatigue 
(50.6%), nausea (40.7%), diarrhea (35.8%), stomatitis (33.3%), vomiting (24.7%), decreased 
appetite (23.5%), hypertension (22.2%), peripheral sensor neuropathy (22.2%), epistaxis 
(19.8%), dysphonia (16.0%), thrombocytopenia (16.0%), alopecia (14.8%), headache 
(12.3%), neutropenia (12.3%), and blood triglycerides increased (11.1%).
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•
Combination Therapy of Tivozanib Hydrochloride and mFOLFOX6: Related TEAEs 
were reported in 17/30 subjects (56.7%). The most frequently reported related TEAEs 
(occurring in ≥10% of treated subjects) were nausea (50.0%), vomiting (36.7%), fatigue 
(40.0%), peripheral sensor neuropathy (33.3%), decreased appetite (30.0%), diarrhea 
(23.3%), stomatitis (23.3%), dysphonia (23.3%), epistaxis (16.7%), neutropenia (13.3%), 
anemia (13.3%), hypertension ( 13.3%), constipation 10.0%), thrombocytopenia (10.0%), 
headache (10.0%), thrombophlebitis (10.0%), and alopecia (10.0%).
Tivozanib hydrochloride has been generally well tolerated. Table 1 lists adverse drug reactions 
that, based upon preliminary safety data from 4 core RCC monotherapy studies, could be 
reasonably assumed to be associated with tivozanib hydrochloride. The incidence of these 
adverse drug reactions to date in 4 core RCC monotherapy studies is also presented. For the 
purposes of regulatory reporting, the preferred terms listed in Table 1 are considered expected 
with tivozanib hydrochloride monotherapy.
Table 1.
Adverse Events Expected to Occur with Tivozanib Hydrochloride Monotherapy
Preferred Term
Safety Population 
N = 712 Subjects
N (%)
Hypertension (including: arterial, worsened, increased, elevated) ≤ CTCAE Grade 31
291 (40.9 %)
Dysphonia/Hoarseness
144 (20.2 %)
Fatigue
132 (18.5 %)
Diarrhea
130 (18.2 %)
Asthenia
118 (16.6 %)
Dyspnea
94 (13.2 %)
Palmar-Plantar Erythrodysesthesia Syndrome ≤ CTCAE Grade 31
67 (9.4 %)
Nausea
63 (8.8 %)
Proteinuria ≤ CTCAE Grade 31
55 (7.7 %)
Stomatitis
55 (7.7 %)
Headache
53 (7.4 %)
Decreased appetite
46 (6.5 %)
Vomiting
38 (5.3 %)
Arthralgia
35 (4.9 %)
Hypothyroidism
23 (3.2 %)
Arterial thromboembolic events (ischemic stroke, myocardial infarction, transient 
ischemic attack, acute myocardial infarction, arterial thrombosis, retinal artery thrombosis, 
and pulmonary artery thrombosis)2
20 (2.8 %)
Venous thromboembolic events (pulmonary embolism, vena cava thrombosis, deep vein 
thrombosis, pelvic venous thrombosis, subclavian vein thrombosis, and thrombophlebitis)2
12 (1.7 %)
Pooled data from 4 core RCC monotherapy studies, AV-951-07-201, AV-951-10-202, AV-951-09-902, and 
AV-951-09-301.
1
The incidence of hypertension, palmar-plantar erythrodysesthesia syndrome, and proteinuria presented in this 
table include events of all grades. For the purposes of regulatory reporting, these events are considered expected 
at ≤ CTCAE Grade 3. Higher grades are considered unexpected.
2
Terms from Standardized MedDRA Query.
When tivozanib hydrochloride is administered in combination with 1 or more approved 
antineoplastic agents, the expectedness determination should take into account the labeling of 
each specific marketed drug taken in combination based upon reference documents that will be 
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included or referenced in the clinical study protocol. The labeled events should, in general, be 
considered expected for at least one of the drugs in the combination. The contribution of 
tivozanib hydrochloride to the severity or frequency of the events is currently unknown.
1.6
Correlative Studies
1.6.1
Pharmacokinetic/ Pharmacokinetic and VEGFR-2
Given the toxicity and cost of newer targeted therapies, an important goal of early phase clinical 
studies is to identify biomarkers that will identify subsets of patients most likely to benefit from 
novel agents as well as to further our understanding of the mechanisms that are not yet not fully 
known. Research in this area has focused on soluble factors such as changes in soluble VEGF 
receptors, dynamic vascular changes and permeability changes using newer functional imaging 
such as DCE-MRI, but no standards have emerged. In a recent study of sunitinib and 
chemoembolization in HCC, we used PK modeling and developed a model using soluble 
VEGFR -2 and AUC of sunitinib and its active metabolite to predict PFS.8 Model predicted PFS 
of 7 months and actual PFS in the study of 7.8 months strongly correlated. Given this finding and 
the very similar mechanism of action between sunitinib and tivozanib, we propose to do a limited 
PK sampling at rationally selected time points to assess both AUC and soluble VEGFR-2 in 
tivozanib treated patients and correlate the PFS at 24 weeks with model predicted outcomes 
using the previously described model. Stats methods are described in appropriate sections. 
Despite this being a good liver function population by inclusion criteria, still represents a 
population with limited liver reserve, hence we are starting at one dose level below 
recommended Phase 2 dose, PK studies in the patients included in this initial Phase 1 portion 
will add to the existing knowledge of tivozanib pharmacokinetic literature and is included for 
patient safety.
1.6.2
Immune Biomarker
Like many other cancers, HCC cells develop multiple strategies of escaping tumor-specific 
immunity such as the accumulation of myeloid-derived suppressor cells (MDSC),9 suppression 
of tumor-associated antigen-reactive lymphocytes by T regulatory cells (Treg)10 and 
dysfunctional dendritic cells.11 MDSCs will be quantified by flow using a panel of markers that 
we have already standardized HLA DR-, CD 14-, CD11b +,CD33+. These mechanisms that 
drive HCC progression makes the development of efficacious immunotherapies for HCC very 
challenging.
The hypothesis of this study is based on the following rationale: c-Kit is one of the targets of 
tivozanib and functions as a receptor for stem cell factor (SCF),12 a well-studied tumor-derived 
factor expressed by various human and murine tumor cell lines.13 In mouse tumor models, 
abrogation of tumor-expressed SCF by RNA interference has been shown to significantly reduce 
MDSC expansion and restore the effector function of tumor-infiltrating T cells.14 Furthermore, 
blockade of c-Kit by immunotherapeutic treatment with an anti-c-Kit monoclonal antibody 
prevented the development of Tregs, tumor-specific T cell anergy and tumor angiogenesis.14 In 
view of this role of c-Kit, we hypothesize that modulation of c-Kit signaling via tivozanib may 
have a novel role in reversing tumor-induced immune suppression. In RPCI studies, levels of 
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ERK2 phosphorylation will be compared between c-Kit+ and c-Kit− immune cells to allow us to 
address the role of c-Kit expression on immune cells as the mechanism by which tivozanib 
modulates the immunosuppressive network in advanced stage HCC patients. Results will be 
correlated to outcome measurements on patients (progressed, median survival time.
Targeting of c-Kit to prevent MDSC and Treg accumulation in murine tumor models has been 
successfully demonstrated with sunitinib.15,16 Importantly, in our studies with HCC patients we 
have shown that multifocal immunosuppressive networks are present at high levels in patients 
compared to healthy controls and that they are reduced following sorafenib treatment (provided 
in Preliminary Data). Specifically, the frequency of MDSCs and Tregs decreased in advanced 
stage HCC patients following their treatment with sorafenib.
The downstream signaling effect of receptor tyrosine kinase (RTK) inhibitors, such as tivozanib, 
is modulation of mitogen-activated protein (MAP) kinase phosphorylation. Although RTKs 
converge on several MAP kinases, this study will examine tivozanib-mediated modulation of 
ERK2 phosphorylation by high-throughput multi-parameter flow cytometry. In addition, this 
study will measure the extent of intracellular ERK2 phosphorylation as this adaptor signaling 
molecule plays a critical role in the function of immunosuppressive and effector immune cells. 
The expression level of c-Kit and level of ERK2 phosphorylation will be examined in circulating 
MDSC and Tregs analyzed from patients with advanced, inoperable hepatocellular carcinoma 
receiving tivozanib as part of a Phase 2 study. One prediction is that ERK2 phosphorylation will 
decrease in c-Kit+ MDSC and Tregs upon treatment with tivozanib. Diminished c-Kit signaling 
will therefore coincide with a reduction in the frequency of MDSC and Tregs relative to effector 
anti-tumor T cells.
1.7
Risks and/or Benefits
The known adverse events from tivozanib include diarrhea, fatigue, asthenia, hypothyroidism, 
dysphonia, hypertension, palmo-plantar erythrodysesthesia, and alopecia. Refer to Table 1 and 
the current Tivozanib Investigator Brochure.
2
RATIONALE
HCC is a common malignancy worldwide and rising in incidence in the United States. Most 
patients have incurable/advanced disease at presentation. The subset of Child Pugh Class A and 
early Class B liver dysfunction patients have been shown to benefit from sorafenib which is 
considered the ‘standard of care’; as it improved overall survival and PFS when compared with 
placebo in well conducted large randomized Phase 3 trials despite a lack of radiographic 
response. The time to symptom improvement endpoint, however, was not met and median 
survival still remains less than 11 months. Targeting angiogenesis is now the backbone of HCC 
therapy, but better agents and biomarkers that define subsets of patients who are likely to derive 
the most benefit from such therapies are still needed. Tivozanib is an oral potent inhibitor of 
VEGFR-1, VEGFR-2, and VEGFR-3 and represents a tolerable and effective treatment for 
VEGF driven malignancies based on data from 12 completed trials in cancer patients. It showed 
safety and efficacy in renal cell cancer and is being evaluated in combination with sorafenib in 
Phase 3 studies in RCC. Given that HCC is a highly vascular VEGF driven malignancy and like 
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RCC, is a malignancy where sorafenib has proven efficacy, we hypothesize tivozanib may have 
meaningful clinical benefit. Although HCC pathogenesis is driven by many factors, of the 
identified angiogenic factors, VEGF is the most potent and specific and has been identified as a 
crucial regulator of both normal and pathologic angiogenesis. In vivo data suggest that VEGF 
inhibition with tivozanib has therapeutic potential in HCC. Elevated VEGF levels correlate with 
advanced stage and poor prognosis in HCC. The preclinical efficacy of tivozanib in HCC 
models, the tolerability in early clinical trials and success of a targeting angiogenesis in HCC 
form the rationale for our hypothesis that tivozanib may be tolerable and improve PFS in HCC 
patients beyond 24 weeks, the expected median PFS for patients receiving sorafenib. In vitro, 
sorafenib has been reported to have anti-HCV effects and in recently completed human studies 
we have seen significant differences in survival using baseline immune cell numbers. It is 
expected that some effects of novel multi-targeted TKIs maybe immune mediated and hence 
propose to test this hypothesis prospectively using validated assays already in place.
3
OBJECTIVES
3.1
Primary Objective
The primary endpoint of the study is PFS at 24 weeks in patients with advanced HCC. Patients 
who remain alive without evidence of disease progression (per RECIST) for at least 24 weeks 
after enrollment will be considered PFS responders.
3.2
Secondary Objectives
•
To determine the safety of tivozanib in HCC.
•
To determine the OS and clinical benefit rate (CR, PR and SD) by RECIST.
•
To determine the steady state PK and soluble VEGFR-2 baseline/ change with tivozanib and 
use modeling to correlate exposure with biomarker change and the primary outcome measure 
of PFS.
•
To determine the change in viral load (HBV and HCV) during therapy in patients with HBV 
or HCV associated HCC.
•
To determine the change in tumor marker (alfa fetoprotein) with tivozanib therapy is in the 
effect of tivozanib on several tumor-associated immune response markers.
3.3
Study Design
This is a multicenter Phase 1b/2 study of tivozanib in patients with advanced inoperable 
hepatocellular carcinoma.
3.3.1
Phase 1b 
Based on monotherapy tolerability data of tivozanib from 14 studies an oral dose of 1.5 mg daily 
has been recommended for Phase 2 testing. Since tivozanib has not been tested in HCC patients, 
and HCC patients who are candidates for systemic therapies tend to have Child Pugh Class A or 
early B cirrhosis, this study will start with a Phase 1 dose escalation study.
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The Phase 1b portion of the study follows a modified 3 + 3 design. Typical 3 + 3 studies start at 
the lowest dose. This modified design starts at patients at the middle dose. The first 3 patients 
will be treated with a 1 mg oral once daily dose. Depending on observed toxicity rates, the dose 
may be deescalated to 0.5 mg, or escalated to 1.5 mg. The standard 3 + 3 dose (de)escalation 
rules will be followed, as specified in the table below.  Dose level will be considered, tolerable 
following completion of 1st cycle of treatment. The dose of 1 mg daily, was found to be the 
tolerated dose in the phase 1b portion and will be the phase 2 dose.
Number of Patients with DLT at a 
Given Dose Level
Escalation Decision rule
0 out of 3
Enter 3 patients at the next higher dose level.
≥ 2 out of 3
Stop dose escalation and declare this dose level as the maximally 
administered dose (highest dose administered).
Enroll 3 additional patients at the next lowest dose level if only 3 patients 
were treated previously at that dose.
1 out of 3
Enter 3 more patients at this dose level.
If 0 of these 3 patients experience DLT, proceed to the next dose level.
If ≥ 1 of this group suffer DLT, then stop dose escalation, and declare this 
dose as the maximally administered dose. Enroll 3 additional patients at 
the next lowest dose level if only 3 patients were treated previously at 
that dose.
≤ 1 out of 6 at the highest dose level 
below the maximally administered 
dose
This is generally the recommended Phase 2 dose. At least 6 patients must 
be entered at the recommended Phase 2 dose
3.3.2
Phase 2
The Phase 2 portion is a two-stage, single arm, unblinded trial allowing for early termination in 
case of futility. The 6 Phase 1b patients treated at the recommended Phase 2 dose will be 
included in the Phase 2 trial. Details are provided in Section 11.
3.3.3
Treatment Cycle
A cycle will be defined as 28 days.  At the full dose, this will be 21 days on treatment with 
7 days off. However, in the case of a dose reduction patients will be treated starting on day 1 of 
the cycle, every other day for 10 doses. Treatment will continue until progression or toxicity. 
Response/ progression will be assessed Q 8 weeks or q 2 months by CT scan. (MRI when 
patients have contraindication to CT). Steady state PK will be assessed at Day 15, as this is the 
first study in patients with liver dysfunction.
3.4
Target Accrual and Study Duration
Between 6 and 18 patients will be enrolled in the Phase 1b portion of this study. Six Phase 1b 
patients treated at the recommended Phase 2 dose will be included in the Phase 2 portion of this 
study. An additional 31 patients will be enrolled for the Phase 2 portion, for a total Phase 2 
sample size of 37. This study is expected to accrue 9 patients to the Phase 1b, for a combined 
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sample of size of 40 (9+37-6). If 18 patients are enrolled in the Phase 1b, the maximum 
combined sample size will be 49 (18+37-6).
Accrual is expected to take up to 4 years. The duration the patient will be on study will be 
approximately 2 years.
4
SUBJECT SELECTION
4.1
Inclusion Criteria
To be included in this study, subjects must meet the following criteria:
1. Advanced staged HCC (unresectable and not amenable to local or regional therapy; or 
metastatic HCC). The diagnosis of HCC should be based on at least one of the following:
•
MRI or CT consistent with liver cirrhosis AND at least one solid liver lesion measuring 
≥ 2 cm, with characteristics arterial enhancement and venous washout regardless of AFP 
levels.
•
AFP ≥ 400 ng/mL AND evidence of at least one solid liver lesion ≥ 2 cm regardless of 
specific imaging characteristics on CT or MRI.
•
Histological/cytology biopsy confirming HCC.
2. Patients must have measurable disease per RECIST 1.1 criteria defined as at least one lesion 
that can be accurately measured in at least one dimension, and that has not been the target of 
local or regional therapy including transarterial chemoembolization, intra-arterial 
chemotherapy, ethanol or radiofrequency ablation.
3. Age ≥ 18 years.
4. Life expectancy of greater than 3 months.
5. Patients must have organ and marrow function as defined below:
•
Child-Pugh liver function Class A. (Appendix G)
•
AST ≤ 5 x Institutional upper limits of normal (ULN)
•
Total bilirubin ≤ 3 mg/dL
•
INR ≤ 2.0 (unless due to therapeutic warfarin use)
•
Serum albumin > 2.8 g/dL
•
Creatinine ≤ 1.5 x Institutional ULN
•
ANC > 1200/mm3
•
Platelets ≥ 60,000/mm3
•
Hgb ≥ 8.5 g/dL
NOTE: The lower absolute neutrophil count (ANC) and platelet cut-offs are designed to 
accommodate the large number of patients with HCC who have portal hypertension and splenic 


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sequestration. Given the adverse profile of tivozanib these reduced cut-offs are thought to be 
safe.
6. Patients must not have any evidence of bleeding diathesis or active gastrointestinal bleeding.
7. Patients must not be known to be HIV positive; drug-drug interaction with study medication 
and HIV medications is not well characterized and could lead to unwanted side effects.
8. Patients must not have other uncontrolled intercurrent illnesses (excluding HBV or HCV). 
This includes (but is not limited to) ongoing or active infection, symptomatic congestive 
heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social 
situations that would limit compliance with study requirements.
9. Sexually active fertile patients (male and female), and their partners, must agree to use 
medically accepted methods of contraception during the course of the study and for 3 months 
after the last dose of the study drug.
10. Female patients of childbearing potential must have a negative pregnancy test at screening.
11. Have an ECOG Performance Status of ≤ 2. Refer to Appendix B.
12. Subject or legal representative must understand the investigational nature of this study and 
sign an Independent Ethics Committee/Institutional Review Board approved written 
informed consent form prior to receiving any study related procedure.
4.2
Exclusion Criteria
Subjects will be excluded from this study for the following:
1. Patients who have had prior anti-angiogenic therapy, including but not limited to sorafenib, 
brivanib, bevacizumab, or sunitinib.
2. Patients who have had any prior line of systemic therapy including cytotoxic agents or 
molecularly targeted agents for advanced/unresectable disease. Any number of prior regional 
therapies with transarterial chemoembolization (TACE), brachytherapy with Yttrium-90 
microsphere, intra-arterial chemotherapy, surgery, or ablative therapy is allowed.
3. Prior liver transplantation and on immunosuppression; drug-drug interaction with study 
medication and immunosuppression is not well characterized and could lead to unwanted 
side effects.
4. Known symptomatic or uncontrolled brain metastases or epidural disease.
5. Patient has a corrected QT interval (QTcF) > 500 ms at screening.
6. The patient is unable to swallow pills or diagnosed with a gastrointestinal disorder that are 
likely to interfere with the absorption of the study drug or with the patient's ability to take 
regular oral medication.
7. The patient is pregnant or breastfeeding.
8. Patients with second primary cancer (except adequately treated nonmelanoma skin cancer, 
curatively treated in-situ carcinoma of the cervix or superficial bladder cancer, or other solid 
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tumors including lymphoma without bone marrow involvement curatively treated with no 
evidence of disease for ≥ 5 years).
9. The patient has a previously identified allergy or hypersensitivity to components of the study 
treatment formulation.
10. Patients receiving any medications or substances that are strong inducers of CYP3A4 are 
ineligible. Moderate and mild inducers of CYP3A4 should be used with caution, as they may 
reduce the efficacy of Tivozanib.
11. Urine protein: creatinine ratio > 1 see (Appendix- H)
4.3
Inclusion of Women and Minorities
Both men and women and members of all races and ethnic groups are eligible for this study.
5
INVESTIGATIONAL PRODUCT
5.1
Active Substance and Source
Tivozanib is formulated for oral administration as a white opaque number 4 gelatin capsule. 
Tivozanib 1 mg, capsules will be used in this study.
5.2
Drug Shipment
Tivozanib, manufactured by AVEO/Astellas Pharmaceuticals, will be shipped to the 
participating site from the drug depot.
Drug shipment records will be retained by the investigational pharmacist or designee.
5.3
Storage and Stability
The Investigator or designate is responsible to store and dispense the investigational product and 
will be responsible for ensuring that study drug is securely maintained in a locked, limited-access 
facility, in accordance with the applicable regulatory requirements.
Tivozanib is to be stored at room temperature (15˚C - 25˚C), in a dry place, and in a secure 
location.
Tivozanib bottle labels will bear the appropriate label text for investigational agents, as required 
by governing regulatory agencies.
Complete study drug information (including packaging, labeling, storage and disposition) is 
provided in the Tivozanib Investigator’s Brochure (IB).
5.4
Handling and Disposal
The Investigator or designee will be responsible for dispensing and accounting for all 
investigational drug, exercising accepted medical and pharmaceutical practices. Study drugs 
must be handled as cytotoxic agents and appropriate precautions taken per the institution’s 
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environmentally safe handling procedures. All investigational drugs will be dispensed in 
accordance with the Investigator’s prescription or written order.
All products dispensed will be recorded on a product accountability record. Records of product 
lot numbers and dates received will be entered on a product accountability form. This record will 
be reviewed by the Sponsor’s staff or representative during periodic monitoring visits. It is the 
Investigator’s responsibility to ensure that an accurate record of investigational drug issued and 
returned is maintained.
Under no circumstances will the Investigator supply investigational drug to a third party or allow 
the investigational drug to be used in a manner other than as directed by this protocol.
6
TREATMENT PLAN
6.1
Preparation and Administration
Treatment will be administered in an outpatient basis. Reported adverse events (AEs) and 
potential risks are described in Section 9. Appropriate dose modifications are described in 
Section 0. No other investigational or commercial drugs or therapies other than that described 
below may be administered with the intent to treat the subject.
The amount of tivozanib 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. Only 
21 capsules will be dispensed per cycle. In the case of a dose reduction patient will be given 10 
capsules for every other day dosing for 10 doses.
Tivozanib capsules will be dispensed for oral use only and taken daily for 21 days and off for 
7 days. The intended dose is 1 mg daily on Day 1 through Day 21 and no drug on Day 22 
through Day 28, in a 28-day cycle. Patients start Cycle 2 after Day 28 and repeat dosing from 
Day 1 to Day 21. In the case of dose reduction patients will be intended to take 1 mg every other 
day starting on Day 1. After 10 doses (every other day) patients will have no drug through the 
end of the 28-day cycle.  Patients will start the next cycle after Day 28 of the previous cycle.
The prescribed daily dose of tivozanib hydrochloride is to be taken, once per day (or every other 
day in the case of a dose reduction), preferably in the morning, with water, and with or without 
food. Only one capsule of tivozanib hydrochloride should be taken each dose. If a dose is 
vomited or otherwise missed that day for any reason, the dose for that day should not be made 
up. The next dose should be taken as prescribed at the next scheduled time (i.e., one capsule is to 
be taken even if the previous dose was vomited or otherwise missed; additional dose(s) should 
not be taken at any time to make up for any missed dose(s)). Grapefruit and grapefruit juice 
should be avoided during the study.
In the event that tivozanib hydrochloride dosing is interrupted, the duration of cycle/treatment 
will not be extended; doses missed during the interruption will be captured as omitted rather than 
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Figure 1.
Dosing Schema
Table 2.
Dose Schedule
Level
Dose
-1*
0.5 mg PO daily for 21 days, then 7 days off (q 28 days cycles)
1 (starting dose)
1 mg PO daily for 21 days, then 7 days off (q 28 days cycles)
2
1.5 mg PO daily for 21 days, then 7 days off (q 28 days cycles)
*0.5 mg not manufactured (Per Amendment #11), please see section 6.2.4
6.2
Dose Modifications
6.2.1
Definition of Dose-Limiting Toxicity 
A DLT is any Grade 3 or higher toxicity that is possible, probable, or definitely related to study 
drug.
Management and dose modifications associated with the above AEs are outlined in the below 
sections. Dose level will be, considered tolerable following completion of 1st cycle of treatment. 
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Patients who experience a DLT will be dose reduced to the next lower dose cohort for 
continuation on the study.
6.2.2
Treatment Delay
Clinical judgment will be used to determine appropriate management of the subject experiencing 
any adverse event (AE). The suggested criteria for dose modification for tivozanib hydrochloride 
drug-related AEs are summarized in the table below.
Table 3.
Tivozanib Hydrochloride Dose Modification Guidelines for Drug-Related Adverse 
Events
Drug-Related Adverse 
Events (excluding 
Hypertension1)
Action Taken
Subsequent Dosing Modification
Grade 1
No dose interruption,  or reduction 
required; adverse event management is 
at the discretion of the Investigator
None required; Dosing may continue at the 
same dose
Grade 2
No dose interruption, or reduction 
required; adverse event management is 
at the discretion of the Investigator
None required; Dosing may continue at the 
same dose
Grade 3
Interrupt dosing until toxicity resolves to 
grade < 1
Dosing may resume at reduced dose (see 
below for dose reduction guidelines)
Grade 4
Interrupt dosing until toxicity resolves to 
grade < 1.
Dosing may resume at reduced dose (see 
below for dose reduction guidelines).
1
Hypertension must be treated as described in Section 6.2.5 prior to any dose modification
6.2.3
Tivozanib Hydrochloride Dose Interruption
Subjects with drug related Grade 3/4 AEs should have their dose interrupted to allow for 
resolution of toxicities to grade < 1. The exception is HTN, which must first, be treated as 
described in Section 6.2.5 prior to any dose modification. Dosing interruptions of ≤ 2 weeks will 
be allowed. Upon resolution of toxicities to ≤ grade 1, dosing may resume at one dose level 
below the current dose, based on the Investigator’s discretion for an individual subject’s safety 
and tolerability. Doses missed during a drug interruption are not to be made up. If dosing is 
interrupted for > 2 weeks, dosing should be discontinued, unless there is clear benefit from 
treatment. 
6.2.4
Tivozanib Hydrochloride Dose Reduction
Dose reductions of tivozanib by 0.5 mg/day will be required for patients with ≥ Grade 3 
drug-related adverse events.  This excludes grade ≥ 3 hypertension, nausea, vomiting, and 
diarrhea, without adequate supportive care.  Hypertension, nausea, vomiting, and diarrhea may 
resume at the same dose level after adequate supportive care, in the investigators opinion it is 
safe to proceed at the same dose level.  If hypertension, diarrhea, nausea, and vomiting recurs 
despite adequate supportive care tivozanib must be dose reduced, up to 2 dose reductions are 
allowed. Once a patient’s dose of tivozanib is reduced, it may not be re-escalated through the 
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remainder of the patient’s participation in the study. 1 mg capsules every other day for 10 doses 
will be used, as 0.5 mg capsules are no longer manufactured. According to the drug manufacturer 
AVEO Pharmaceuticals, this dosing regimen will achieve comparable exposure to 0.5 mg QD, 
based on the half-life of Tivozanib. 
6.2.5
Management of Hypertension
Hypertension (HTN) that occurs during study treatment must be treated with anti-hypertensive 
drugs prior to any dose reduction. Recommended management of HTN for subjects receiving 
study drug is presented in Appendix C and Appendix D.
Persistent HTN is defined as 2 consecutive elevated blood pressure (BP) measurements 
preferably taken in the clinic and obtained at least 1 hour apart. It is recommended that 
24-48 hours should elapse between the decision steps. For a listing of recommended DHP 
(dihydropyridine) calcium channel blockers, angiotensin converting enzyme (ACE) inhibitors, 
and angiotensin receptor blockers, see Appendix D, Recommended Anti-hypertensive 
Medications. Note: If a subject has controlled HTN on an anti-hypertensive regimen at baseline 
and then develops a worsening of HTN requiring more intensive therapy than the previous 
regimen, this would be considered Grade 3 HTN.
6.3
General Concomitant Medication and Supportive Care
Agents known to be Cytochrome P450 (CYP3A4) strong inhibitors and inducers must be 
avoided for the duration of tivozanib treatment. Appropriate replacement drugs will be 
prescribed with the help of clinical Pharmacist. An individual patient’s risk/benefit should be 
taken into account when administration of a CYP3A4 inhibitor or inducer is required as these 
agents may decrease serum concentrations of tivozanib, potentially impairing efficacy. For a 
complete 
list 
and 
additional 
information, 
refer 
to 
the 
following 
website: 
http://medicine.iupui.edu/clinpharm/ddis/table.aspx.
Since there is a potential for interaction of tivozanib with other concomitantly administered 
drugs through the CYP3A4 system, the electronic case report form (eCRF) must capture the 
concurrent use of all other drugs, over-the-counter medications, or alternative therapies. The 
Investigator should be alerted if the patient is taking any agent known to affect or with the 
potential to affect selected CYP450 inhibitors and inducers.
Patients may be pretreated for nausea and vomiting with appropriate anti-emetics.
6.4
Treatment Discontinuation
Patients with non-hematologic Grade 4 drug related adverse events will permanently discontinue 
study drug unless the patient has experienced objective evidence of benefit and the investigator 
has determined that it is reasonably safe to continue treatment despite the occurrence of a life 
threatening adverse event.  If a patient has dose interruption ≤ 2 weeks from the next scheduled 
dose, missed doses will not be made up (i.e., cycle duration will remain unchanged). If any drug-
related toxicity results in interruption of dosing of > 2 weeks from the next scheduled dose, the 
subject should be discontinued from tivozanib, unless there is clear benefit from treatment.
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Upon treatment discontinuation, all end of study evaluations and tests will be conducted. All 
subjects who discontinue due to an AE must be followed until the event resolves or stabilizes. 
Appropriate medical care should be provided until signs and symptoms have abated, stabilized, 
or until abnormal laboratory findings have returned to acceptable or pre-study limits. The final 
status of the AE will be reported in the subject’s medical records and the appropriate eCRF.
Reasons for treatment discontinuation should be classified as follows:
•
Death
•
Progressive disease
•
Treatment-related toxicity
•
Toxicity unrelated to treatment
•
Investigator judgment
o
The Investigator may withdraw a subject if, in his/her judgment, it is in the 
subject’s best interest to do so.
•
Noncompliance
•
Subject voluntary withdrawal
o
A subject may withdraw from the study at any time, for any reason. If a subject 
discontinues treatment, an attempt should be made to obtain information 
regarding the reason for withdrawal.
•
Early withdrawal of subject(s)
•
Sponsor decision.
6.5
Compliance
Patients will be instructed to record date for each day and the total number of pills taken each 
day (Appendix E). Dosing compliance will be monitored at each clinic visit. Phase 1b patients 
who do not complete at least 80% of the prescribed dose in Cycle 1 for reasons other than DLT 
will be replaced. Otherwise, if a patient has 2 consecutive cycles of less than 50% compliance, 
the patient will be deemed non-compliant and come off study. At the discretion of the 
investigator, if the patient is benefiting from the treatment the patient may continue on study. 
Patients who come off study, due to non-compliance, will not be replaced.
7
STUDY PROCEDURES
7.1
Baseline Evaluations
The following will be performed within 2 weeks prior to treatment start and prior to receiving 
any study-related procedures:
•
Informed consent: Must be completed prior to receiving any study-related procedures.
•
Medical history
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•
Physical examination, including vital signs (i.e., temperature, heart rate, respiratory rate, 
blood pressure, body weight, and height)
•
Hematology (i.e., complete blood count (CBC) with differential, absolute neutrophil count 
(ANC), and platelets)
•
Chemistry (comprehensive metabolic panel (i.e., AST, ALT, total bilirubin, alkaline 
phosphatase, creatinine, potassium, glucose, and calcium) and serum albumin.
•
Alpha-Fetoprotein (AFP)
•
PT/INR 
•
Urine pregnancy test in females of childbearing potential (performed within 1 week prior to 
treatment start).
•
ECOG Performance Status
•
Electrocardiogram
•
CT Scan- (within 4 weeks)
•
Concomitant Medications (Any ongoing medications with an onset within 1 week of first 
dose of study drug.)
•
Hep B and C testing (if unknown). Blood collection of about 4 teaspoons will be drawn from 
your arm for HBsAg, (the surface antigen of the hepatitis B virus (HBV). And Hep C Ab 
with verification. 
•
 Urine will be collected to calculate urine protein and creatinine ratio. 
7.2
Evaluations Performed at Cycle 1, Day 1
•
Physical examination, including vital signs (i.e., temperature, heart rate, respiratory rate, 
blood pressure, and body weight)
•
Hematology (i.e., CBC with differential, ANC, and platelets)
•
Chemistry (comprehensive metabolic panel (i.e., AST, ALT, total bilirubin, alkaline 
phosphatase, creatinine, potassium, glucose, and calcium) and serum albumin.
•
PT/INR 
•
Pharmacokinetic/Pharmacodynamic sVEGF-2 Sampling
•
Immune Biomarker Sampling
•
ECOG Performance Status
•
Tivozanib (Patients will be administered tivozanib in clinic following their pre-dose 
pharmacokinetic/pharmacodynamic sample).
•
Concomitant Medications
•
If either (or both) HBsAg or Hep C Ab with verification are positive, blood will be collected 
for viral load anytime pre-treatment. (Viral load test: Hep B (or C) virus PCR, Quant).
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7.3
Evaluations Performed at Cycle 1, Day 15 (± 3 Days)
•
Physical examination, including vital signs (i.e., temperature, heart rate, respiratory rate, 
blood pressure, and body weight)
•
Hematology (i.e., CBC with differential, ANC, and platelets)
•
Chemistry (comprehensive metabolic panel (i.e., AST, ALT, total bilirubin, alkaline 
phosphatase, creatinine, potassium, glucose, and calcium) and serum albumin.
•
PT/INR 
•
Pharmacokinetic/Pharmacodynamic sVEGF-2 Sampling
•
ECOG Performance Status
•
Tivozanib (Patients will be administered tivozanib in clinic following their pre-dose 
pharmacokinetic/pharmacodynamic sample).
•
Concomitant Medications
•
Adverse Events
7.4
Evaluations Performed at Day 1 of Each Cycle After Cycle 1 (± 3 Days)
•
Physical examination, including vital signs (i.e., temperature, heart rate, respiratory rate, 
blood pressure, and body weight)
•
Hematology (i.e., complete blood count (CBC) with differential, absolute neutrophil count 
(ANC), and platelets)
•
Chemistry (comprehensive metabolic panel (i.e., AST, ALT, total bilirubin, alkaline 
phosphatase, creatinine, potassium, glucose, and calcium) and serum albumin.
•
PT/INR 
•
ECOG Performance Status
•
Tivozanib (Patients will take at home).
•
Concomitant Medications
•
Adverse Events
•
Alpha Fetoprotein (AFP): Biomarker to detect hepatocellular cancer every 2 cycles, starts 
with cycle 3 (Only if elevated at baseline).
•
A computed tomography scan (CT scan) every 2 cycles, not to exceed 10 weeks apart.
•
Urine will be collected to look at protein and creatinine levels every 2 cycles starting with 
cycle 3 
•
If either (or both) HBsAg or Hep C Ab with verification are positive, blood will be collected 
for viral load, (Hep B (or C) virus PCR, Quant) every 2 cycles  starting with cycle 3 
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7.5
Evaluations Performed at Cycle 3, Day 1 (± 3 Days)
•
Physical examination, including vital signs (i.e., temperature, heart rate, respiratory rate, 
blood pressure, and body weight)
•
Hematology (i.e., CBC with differential, ANC, and platelets)
•
Chemistry (comprehensive metabolic panel (i.e., AST, ALT, total bilirubin, alkaline 
phosphatase, creatinine, potassium, glucose, and calcium) and serum albumin.
•
ECOG Performance Status
•
AFP (Only test if AFP was elevated at baseline).
•
PT/INR 
•
Immune Biomarker Sampling
•
CT Scan
•
Concomitant Medications
•
Adverse Events
•
Urine will be collected to look at protein and creatinine levels every 2 cycles starting with 
cycle 3
•
If either (or both) HBsAg or Hep C Ab with verification are positive, blood will be collected 
for viral load. (Viral load test: Hep B (or C) virus PCR, Quant)
7.6
Evaluations Performed at 1 Year (± 7 Days)  
•
Immune Biomarker Sampling (When the patient progresses/comes off study drug or at 1 year 
whichever occurs first.)
7.7
Evaluations Performed at End of Treatment
•
Physical examination, including vital signs (i.e., temperature, heart rate, respiratory rate, 
blood pressure, and body weight)
•
Hematology (i.e., CBC with differential, ANC, and platelets)
•
Chemistry (comprehensive metabolic panel (i.e., AST, ALT, total bilirubin, alkaline 
phosphatase, creatinine, potassium, glucose, and calcium) and serum albumin.
•
CT Scan (Only if last CT scan was more than 28 days prior to end of treatment.)
•
PT/INR 
•
Immune Biomarker Sampling (When the patient progresses/comes off study drug or at 1 year 
whichever occurs first.)
•
ECOG Performance Status
•
Concomitant Medications
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•
Adverse Events
7.8
Follow-Up: Medical Record review every 6 months for overall survival.
7.9
Schedule of Procedures and Observations
The schedule of procedures and observations for this study is summarized in Table 4 below.
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Table 4.
Schedule of Procedures and Observations
Evaluation
Baseline
Cycle 1
Day 1
Cycle 1
Day 15
(± 3 days)
Day 1 of 
Each 
Cycle 
After 
Cycle 1
(± 3 days)
Cycle 3
Day 1
(± 3 days)
1 Year
(± 7 days)
End  of 
Treatment15 
Informed Consent
X
Medical History
X1
Physical Examination , including 
vital signs (i.e., temperature, heart 
rate, respiratory rate, blood 
pressure, body weight, and height)2
X1
X
X
X
X
X
Hematology3
X1
X
X
X
X
X
Chemistry4
X1
X
X
X
X
X
HBsAg17
X
Hep C Ab With Verification17 
X
Viral Load (Hep B(or C) virus PCR, 
Quant)
X13
X13, 14
X 13, 14
Alpha-Fetoprotein (AFP)
X1
X5,14
X5, 14
PT/INR
X1
X
X
X
X
X
Pharmacokinetic/Pharmacodynamic 
and sVEGF-2 Sample Collection
X6
X6
Immune Biomarker Sample 
Collection
X7
X7
X7
X7
Pregnancy Test (Urine)
X8,1
Urine Protein/Creatinine ratio
X1
X14
X14
ECOG Performance Status
X1
X
X
X
X
X
Electrocardiogram
X1
CT Scan
X16
X12
X12
X9
Tivozanib
X10
X10
X


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Evaluation
Baseline
Cycle 1
Day 1
Cycle 1
Day 15
(± 3 days)
Day 1 of 
Each 
Cycle 
After 
Cycle 1
(± 3 days)
Cycle 3
Day 1
(± 3 days)
1 Year
(± 7 days)
End  of 
Treatment15 
Concomitant Medications
X11,1
X
X
X
X
X
Adverse Events
X
X
X
X
1
Performed within 2 weeks prior to treatment start and prior to receiving any study-related procedures.
2
Height collected at baseline only.
3
Hematology (i.e., complete blood count (CBC) with differential, absolute neutrophil count (ANC), and platelets).
4
Chemistry (comprehensive metabolic panel (i.e.; AST, ALT, total bilirubin, alkaline phosphatase, creatinine, 
potassium, glucose, and calcium) and serum albumin).
5
Only test if AFP was elevated at baseline.
6
Refer to Section 7.10.
7
Pre-dosed cycle 1 day 1, cycle 3 day 1,when the patient progresses/comes off study drug or at 1 year whichever 
occurs first. Refer to Section 7.11.
8
Performed within 1 week prior to treatment start.
9
Only if last CT scan was more than 28 days prior to end of treatment.
10
Patients will be administered tivozanib in clinic following their pre-dose pharmacokinetic/pharmacodynamic 
sample.
11
Medications ongoing within 1 week prior to first dose of study drug.
12
CT every 2 cycles starting with cycle 3, with maximum of 10 weeks apart.
13
Collect viral load, pre-treatment, if either (or both) HBsAg or Hep C Ab with verification are positive & every 2 
cycles starting with cycle 3.
14
Every 2 cycles starting with cycle 3. 
15
Patients will be followed for overall survival, every 6 months by medical record review
16
CT scan within 4 weeks prior to treatment start.
17
Only if unknown


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7.10 Pharmacokinetic/Pharmacodynamic Blood Sample Collection and Processing
Plasma blood samples for pharmacokinetic/pharmacodynamic analysis of tivozanib levels will be 
collected via venipuncture using (2) 4 mL purple-top EDTA collection tubes per time point for 
PK and blood samples for sVEGF-2. 
Pharmacokinetic/pharmacodynamic and sVEGF-2 sample collection will be obtained on:
•
Cycle 1, Day 1 at pre-dose, 2 hours, and 4 hours post-dose.
•
Cycle 1, Day 15 at pre-dose, 2 hours, and 4 hours post-dose.
Plasma will be separated from the total blood within 30 minutes following the extraction. The 
screw cap polypropylene cryogenic tube will be labeled with the subject identifier, subject’s 
initials, subject’s study number, clinical study number, protocol time point, dose, and protocol 
day. The label for each subject’s sample will be supplied by RPCI. The samples will be placed in 
ice immediately and then frozen at -70ºC or below until analyzed. After hours, samples will be 
processed in Lab Medicine.
NETWORK SITES: Follow directions above for sample collection and processing. The 
cryogenic tubes should be labeled with the Subject ID # (unique to Network patients), initials, 
the participant’s study number, clinical study number, protocol time point, dose, and protocol 
day. The samples will immediately be frozen at -70ºC or below (samples are to be stored until 
requested for batch mailing). Samples are to be batch shipped frozen, on dry ice.
Frozen samples will be shipped via Fed Express Overnight on dry ice with delivery on Mon-Fri. 
NO SATURDAY DELIVERY. Do not ship on a Friday or the day before a holiday.
Address shipments and any questions regarding specimen processing to:
Roswell Park Cancer Institute
Bioanalytics, Metabolomics & Pharmacokinetics Core Facility
Center for Genetics and Pharmacology, Room L1-140
Refer to Study Number– I 229112
Elm & Carlton Streets
Buffalo, New York 14263
PKPDCore@RoswellPark.org
For additional information regarding the handling of pharmacokinetic samples please contact 
RPCI’s Bioanalytics, Metabolomics & Pharmacokinetics Core Facility laboratory at 
716-845-3303 (Tel) or 716-845-1579 (Fax).
Note: All investigator or analyzing research laboratories housing research samples need to 
maintain current Temperature Logs and study-specific Sample Tracking and Shipping Logs. 
The Principal Investigator/Laboratory Manager must ensure that the stated lab(s) have a process 
in place to document the receipt/processing/storage/shipping of study-related samples/specimens. 
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This is required for both observational and interventional clinical studies collecting clinical 
samples.
7.11 Immune Biomarker Blood Sample Collection and Processing
Blood samples for measuring immune correlatives by flow cytometry will be collected via 
venipuncture using (4) 10 mL green-top heparinized collection tubes. Tubes must be completely 
filled, and kept at room temperature until processing. Tube will be labeled with the subject 
identifier, subject’s initials, subject’s study number, clinical study number, protocol time point, 
and protocol day. The label for each subject’s sample will be supplied by RPCI. Peripheral blood 
mononuclear cells (PBMC) will be isolated immediately by Ficoll-PaqueTM PLUS density 
gradient centrifugation of blood samples. Refer to Appendix F2.
Patient Pill Diary(Dose Reduced)
Study No.: ____________________
Patient’s Name: ______________________________
Drug Name: __________________
Cycle:______________________
Medical Record No.: ___________
Study Medication Calendar for Tivozanib
You should swallow your medication, unchewed, with a large glass of water (about 8 oz.) in the morning every day with or 
without food. On days of a scheduled clinic visit, you should take your dose at the clinic after visit procedures are completed. If a 
dose is vomited or if you miss your dose for any reason, the dose should not be made up.
Please complete this calendar on a daily basis immediately after you take your pills. Fill in the date for each day and write the 
total number of pills you take each day.
Start Date: _________________
Take 1 pill each time.
Cycle Day
Day 1**(dose1)
Day 2
Day3(dose2)
Day 4
Day5(dose3)
Day 6
Day7(dose4)
Time
Date
Number of 
pills taken
Cycle Day
Day 8
Day 9(dose5)
Day 10
Day11(dose6)
Day 12
Day13(dose7)
Day 14
Time
Date
Number of 
pills taken
Cycle Day
Day15(dose8)
Day 16
Day17(dose9)
Day 18
Day19(dose10)
Day 20
Day 21
Time
Date
Number of 
pills taken
Cycle Day
Day 22
Day 23
Day 24
Day 25
Day 26
Day 27
Day 28
Date
Number of 
pills taken
No medication is to be taken during this time.
**Do NOT take your pill on Day 1 until your blood is drawn and the study staff instructs you to take it.
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Please remember to bring this calendar and your pill bottle (including any unused pills) with you to your next clinic 
appointment.
Coordinator’s Use Only
	
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   !!
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  

   !!
Patient’s Signature:__________________________________________
Date:____________
CRC Signature:_____________________________________________
Date:____________
Investigator Signature:_______________________________________
Date:___________
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Appendix G for the SOP for PBMC isolation. 
Sample collection will be obtained on: Tube station 611
•
Predose on Cycle 1, Day 1
•
Cycle 3, Day 1
•
When the patient progresses/comes off study drug or at 1 year whichever occurs first.
For patients enrolled at RPCI, four 10 mL green-top heparinized blood collection tubes will be 
sent to tube station 611 for processing on the same day. PBMCs from the tubes will be isolated 
by members of the Thanavala laboratory according to the SOP in Appendix F (Section 1). Cells 
will be stored in liquid nitrogen at RPCI as described in Appendix F Section 2 & 3. PMBCs will 
be analyzed by members of the Thanavala laboratory when all three samples from an individual 
patient are available in order to minimize assay variability.
For patients enrolled at Network Sites, four 10 ml green-top heparinized blood collection tubes 
will be processed on the same day at the Network Site. PBMCs will be isolated by trained, 
designated staff at the Network Site according to the SOP in Appendix F (Section 1). Cells will 
be stored in liquid nitrogen at the Network Site as described in Appendix F (Section 2 & 3). 
PMBCs will be shipped to RPCI via Federal Express overnight delivery on dry ice (Monday – 
Thursday only) when all three samples from an individual patient are available. 
For Network sites, batched samples must be shipped overnight on dry ice Monday – Thursday 
only via Federal Express delivery. There is NO SATURDAY DELIVERY. Do not ship on a 
Friday or the day before a holiday.
Yasmin Thanavala, PhD
Roswell Park Cancer Institute
Department of Immunology, Room L5-302
Center for Genetics and Pharmacology
Elm & Carlton Streets
Buffalo, New York 14263
For additional information regarding the handling of laboratory samples please contact RPCI’s 
Thanavala 
Laboratory 
at 
716-845-8536, 
716-845-8535, 
716-845-4592 
or 
Yasmin.Thanavala@RoswellPark.org.
Isolated PBMCs will be stored in liquid nitrogen in 90% human AB serum plus 10% DMSO. All 
3 samples from an individual patient will be analyzed simultaneously to minimize assay 
variability. Extensive testing has been performed to compare fresh and frozen thawed samples 
for reproducibility and to ensure that the process of freezing does not influence the viability of 
cells types being evaluated. FACS analysis on the various cell subsets will be performed as 
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described in detail in the study methodology section. Plasma samples will be stored at −80˚C for 
future measurement of inflammatory and immunosuppressive cytokines.
Clinical therapy, outcome and baseline demographic data will be recorded and stored in the 
RPCI clinical research database. These will be merged with immune data analyzed in blinded 
fashion and provided to the statistician for analysis.
Note: All investigator or analyzing research laboratories housing research samples need to 
maintain current Temperature Logs and study-specific Sample Tracking and Shipping Logs. 
The Principal Investigator/Laboratory Manager must ensure that the stated lab(s) have a process 
in place to document the receipt/processing/storage/shipping of study-related samples/specimens. 
This is required for both observational and interventional clinical studies collecting clinical 
samples.
8
EFFICACY EVALUATIONS
8.1
Objective Tumor Response
All protocol-defined imaging studies must be performed at the investigative site or sponsor-
approved facility using protocol-defined parameters. The same method of assessment and the 
same technique should be used to characterize each identified and reported lesion at baseline and 
during follow-up. RECIST 1.1 will be used to assess objective tumor response.
8.2
Target Lesions
All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, 
representative of all involved organs, will be identified as target lesions and recorded and 
measured at baseline. Target lesions will be selected on the basis of their size. Lesions with the 
longest diameter (short axis for lymph nodes) and are ≥ 10 mm (CT and MRI), ≥ 15 mm lymph 
nodes, > 20 mm CXR and are for accurate repetitive measurements (either by imaging 
techniques or clinically) will be chosen. A sum of the longest diameter (short axis for lymph 
nodes) of all target lesions will be calculated and reported as the baseline sum diameters. This 
will be used as reference to further characterize the objective tumor response of the measurable 
dimension of the disease.
•
Complete Response (CR): Disappearance of all target lesions. Any lymph nodes must have 
a reduction in short axis to < 10 mm. Changes in tumor measurements must be confirmed by 
repeat studies performed no less than 6 weeks after the criteria for response are first met.
•
Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, 
taking as reference the baseline sum diameters. Changes in tumor measurements must be 
confirmed by repeat studies performed no less than 6 weeks after the criteria for response are 
first met.
•
Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, 
taking as references 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 


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an absolute increase of at least 5 mm. 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 diameter while on study. Subjects having 
a documented response with no confirmation of the response will be listed with stable 
disease.
8.3
Non-Target Lesions
All other small lesions (longest diameter < 10 mm or lymph nodes ≥ 10 mm to < 15 mm short 
axis) and non-measurable lesions (i.e., leptomeningeal disease, ascites, pleural or pericardial 
effusion, inflammatory breast disease, lymphangitic involvement of skin or lung, blastic bone 
lesions, or abdominal masses / abdominal organomegaly identified by physical exam that is not 
measurable by imaging) should be identified as non-target lesions and indicated as present in the 
source documents at baseline. The general location will also be documented on the images 
drawing a regularly-shaped Region of Interest. Measurements of the non-target lesions will not 
be performed, but the presence or absence of each should be noted throughout follow-up and 
evaluation.
•
Complete Response: Disappearance of all non-target lesions and normalization of tumor 
marker level, if applicable. All lymph nodes must be non-pathological in size (< 10 mm short 
axis).
•
Non-Complete Response/Non-Progressive Disease: Persistence of 1 or more non-target 
lesion(s) and/or maintenance of tumor marker level above the upper limits of normal.
•
Progressive Disease: Appearance of 1 or more new lesions or the unequivocal progression 
of existing non-target lesions. Although a clear progression of non-target lesions is 
exceptional, in such circumstances, the opinion of the treating physician should prevail and 
the progression status should be confirmed at a later time.
8.4
Evaluation of Response
Time point response assessments will be performed every 8 weeks (timed to coincide with the 
end of a cycle) with a confirmatory assessment (required for non-randomized trials) within 
6 weeks after a PR or CR is deemed. To determine time point response, refer to Table 5 and 
below.
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Table 5.
Time Point Response Criteria (+/- non-target disease)
Target Lesions
Non-Target Lesions
New Lesions
Overall Response
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
Table 6.
Time Point Response Criteria (non-target disease only)
Non-Target Lesions
New Lesions
Overall Response
CR
No
CR
Non-CR/non-PD
No
Non-CR/non-PD1
Not all evaluated
No
NE
Unequivocal PD
Yes or No
PD
Any
Yes
PD
1
Non-CR/non-PD is preferred over SD for non-target disease since SD is used as endpoint for assessment of 
efficacy in trials so to assign this category when no lesions can be measured is not advised.
The best overall response is the best response recorded from the start of study treatment until the 
end of treatment taking into account any requirement for confirmation. In general, the subject’s 
best response assignment will depend on the achievement of both measurement and confirmation 
criteria and will be determined by combining the subject’s status of target lesions, non-target 
lesions, and new lesions.
•
Residual Disease: Any measurable tumor that was considered a target or non-target or new 
lesion ≥ 1 cm.
•
Symptomatic Deterioration: Subjects with global deterioration of health status requiring 
discontinuation of treatment without objective evidence of disease progression at that time, 
and not related to study treatment or other medical conditions should be reported as 
progressive disease due to “symptomatic deterioration.” Every effort should be made to 
document objective progression even after discontinuation of treatment due to symptomatic 
deterioration. Symptomatic deterioration that may lead to discontinuation of treatment 
include, but is not limited to, symptoms such as:
o
Weight loss > 10% of body weight.
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o
Worsening of disease-related symptoms (e.g., worsening dyspnea, increasing 
pain/increasing requirement for narcotic analgesics).
o
Decline in performance status of > 1 level on ECOG scale.
8.5
Confirmation Measurement
Response will be confirmed within 6 weeks.
8.6
Guidelines for Evaluation of Measurable Disease
All measurements should be taken and recorded in metric notation using a ruler or calipers. All 
baseline evaluations should be performed as closely as possible to the beginning of treatment and 
never more than 4 weeks before the beginning of the treatment.
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 
preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam.
•
Clinical Lesions: Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) and ≥ 10 mm diameter as assessed 
using calipers (e.g., skin nodules). In the case of skin lesions, documentation by color 
photography, including a ruler to estimate the size of the lesion, is recommended.
•
Chest x-ray: Lesions on chest x-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung. However, CT is preferable.
•
Conventional CT and MRI: This guideline has defined measurability of lesions on CT scan 
based on the assumption that CT slice thickness is 5 mm or less. If 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 (e.g., for body scans).
Use of MRI remains a complex issue. MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which greatly 
impact image quality, lesion conspicuity, and measurement. Furthermore, the availability of MRI 
is variable globally. As with CT, if an MRI is performed, the technical specifications of the 
scanning sequences used should be optimized for the evaluation of the type and site of disease. 
Furthermore, as with CT, the modality used at follow-up should be the same as was used at 
baseline and the lesions should be measured/assessed on the same pulse sequence. It is beyond 
the scope of the RECIST guidelines to prescribe specific MRI pulse sequence parameters for all 
scanners, body parts, and diseases. Ideally, the same type of scanner should be used and the 
image acquisition protocol should be followed as closely as possible to prior scans. Body scans 
should be performed with breath-hold scanning techniques, if possible.
•
PET-CT: At present, the low dose or attenuation correction CT portion of a combined PET-
CT is not always of optimal diagnostic CT quality for use with RECIST measurements. 
However, if the site can document that the CT performed as part of a PET-CT is of identical 
diagnostic quality to a diagnostic CT (with IV and oral contrast), then the CT portion of the 
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PET-CT can be used for RECIST measurements and can be used interchangeably with 
conventional CT in accurately measuring cancer lesions over time. Note, however, that the 
PET portion of the CT introduces additional data which may bias an investigator if it is not 
routinely or serially performed.
•
Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement. Ultrasound examinations cannot be reproduced in their entirety for 
independent review at a later date and, because they are operator dependent, it cannot be 
guaranteed that the same technique and measurements will be taken from one assessment to 
the next. 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.
•
Endoscopy, Laparoscopy: The utilization of these techniques for objective tumor evaluation 
is not advised. However, such techniques may be useful to confirm complete pathological 
response when biopsies are obtained or to determine relapse in trials where recurrence 
following complete response (CR) or surgical resection is an endpoint.
•
Tumor Markers: Tumor markers alone cannot be used to assess response. If markers are 
initially above the upper normal limit, they must normalize for a subject to be considered in 
complete clinical response.
•
Cytology, Histology: These techniques can be used to differentiate between partial responses 
(PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor types, such as 
germ cell tumors, where known residual benign tumors can remain).
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment when the measurable tumor has met criteria for response or stable disease is 
mandatory to differentiate between response or stable disease (an effusion may be a side effect of 
the treatment) and progressive disease.
•
FDG-PET: While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in 
assessment of progression (particularly possible 'new' disease). New lesions on the basis of 
FDG PET imaging can be identified according to the following algorithm:
•
Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD based 
on a new lesion.
•
No FDG-PET at baseline and a positive FDG-PET at follow-up: If the positive FDG-PET at 
follow-up corresponds to a new site of disease confirmed by CT, this is PD. If the positive 
FDG-PET at follow-up is not confirmed as a new site of disease on CT, additional follow-up 
CT scans are needed to determine if there is truly progression occurring at that site (if so, the 
date of PD will be the date of the initial abnormal FDG-PET scan). If the positive FDG-PET 
at follow-up corresponds to a pre-existing site of disease on CT that is not progressing on the 
basis of the anatomic images, this is not PD.
•
FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy in 
cases where a residual radiographic abnormality is thought to represent fibrosis or scarring. 
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The use of FDG-PET in this circumstance should be prospectively described in the protocol 
and supported by disease-specific medical literature for the indication. However, it must be 
acknowledged that both approaches may lead to false positive CR due to limitations of FDG-
PET and biopsy resolution/sensitivity.
Note: A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake greater 
than twice that of the surrounding tissue on the attenuation corrected image.
9
SAFETY EVALUATION
9.1
Adverse Events
9.1.1
Definition
An adverse event or adverse experience (AE) is any untoward medical occurrence associated 
with the use of a drug in humans, whether or not considered drug related. Therefore, an AE can 
be ANY unfavorable and unintended sign (including an abnormal laboratory finding), symptom, 
or disease temporally associated with the use of a medicinal (investigational) product, whether or 
not considered related to the medicinal (investigational) product (attribution of ‘unrelated’, 
‘unlikely’, ‘possible’, ‘probable’, or ‘definite’).
An AE is considered “unexpected” if it is not listed in the investigator brochure or is not listed at 
the specificity or severity that has been observed; or if an investigator brochure is not required or 
available, is not consistent with the risk information described in the general investigational plan 
in other study-related documents.
9.1.1.1 Diagnosis Versus Signs and Symptoms
If known, a diagnosis should be recorded on the CRF rather than individual signs and symptoms 
(e.g., record only liver failure or hepatitis rather than jaundice, asterixis, and elevated 
transaminases). However, if a constellation of signs and/or symptoms cannot be clinically 
characterized as a single diagnosis or syndrome at the time of reporting, each individual event 
should be recorded as an AE or SAE on the CRF. If a diagnosis is subsequently established, it 
should be reported as follow-up information.
9.1.1.2 Adverse Events Occurring Secondary to Other Events
In general, AEs occurring secondary to other events (e.g., cascade events or clinical sequelae) 
should be identified by their primary cause. For example, if severe diarrhea is known to have 
resulted in dehydration, it is sufficient to record only diarrhea as an AE or SAE on the CRF.
However, clinically significant AEs occurring secondary to an initiating event that are separated 
in time should be recorded as independent events on the CRF. For example, if a severe 
gastrointestinal hemorrhage leads to renal failure, both events should be recorded separately on 
the CRF.
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9.1.1.3 Abnormal Laboratory Values
Only clinically significant laboratory abnormalities that require active management will be 
recorded as AEs or SAEs on the CRF (e.g., abnormalities that require study drug dose 
modification, discontinuation of study treatment, more frequent follow-up assessments, further 
diagnostic investigation, etc.).
If the clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., alkaline phosphatase and bilirubin 5 x the upper limit of normal associated with 
cholecystitis), only the diagnosis (e.g., cholecystitis) needs to be recorded on the Adverse Event 
CRF.
If the clinically significant laboratory abnormality is not a sign of a disease or syndrome, the 
abnormality itself should be recorded as an AE or SAE on the CRF. If the laboratory abnormality 
can be characterized by a precise clinical term, the clinical term should be recorded as the AE or 
SAE. For example, an elevated serum potassium level of 7 mEq/L should be recorded as 
“hyperkalemia”
Observations of the same clinically significant laboratory abnormality from visit to visit should 
not be repeatedly recorded as AEs or SAEs on the CRF, unless their severity, seriousness, or 
etiology changes.
9.1.1.4 Preexisting Medical Conditions (Baseline Signs and Symptoms)
A preexisting medical condition should be recorded as an AE or SAE only if the frequency, 
severity, or character of the condition worsens during the study. When recording such events on 
an Adverse Event CRF, it is important to convey the concept that the preexisting condition has 
changed by including applicable descriptors (e.g., “more frequent headaches”).
9.1.2
Grading and Relationship to Drug
The descriptions and grading scales found in the CTEP Version 4 of the NCI Common 
Terminology Criteria for Adverse Events (CTCAE) will be utilized for AE reporting. CTEP 
Version 4 
of 
the 
CTCAE 
is 
identified 
and 
located 
at: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
AEs not covered by specific terminology listed should be reported with common medical 
terminology, and documented according to the grading scales provided in the CTCAE Version 4.
The relationship of event to study drug will be documented by the Investigator as follows:
•
Unrelated: The event is clearly related to other factors such as the subject’s clinical state, 
other therapeutic interventions or concomitant drugs administered to the patient.
•
Unlikely: The event is doubtfully related to investigational agent(s). The event was most 
likely related to other factors such as the patient’s clinical state, other therapeutic 
interventions, or concomitant drugs.
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•
Possible: The event follows a reasonable temporal sequence from the time of drug 
administration, but could have been produced by other factors such as the patient’s clinical 
state, other therapeutic interventions or concomitant drugs.
•
Probable: The event follows a reasonable temporal sequence from the time of drug 
administration, and follows a known response pattern to the study drug. The event cannot be 
reasonably explained by other factors such as the patient’s clinical state, therapeutic 
interventions or concomitant drugs.
•
Definite: The event follows a reasonable temporal sequence from the time of drug 
administration, follows a known response pattern to the study drug, cannot be reasonably 
explained by other factors such as the patient’s condition, therapeutic interventions or 
concomitant drugs; AND occurs immediately following study drug administration, improves 
upon stopping the drug, or reappears on re-exposure.
9.1.3
Reporting Adverse Events (Network Sites see Appendix A )
Table 7.
Guidelines for Routine Adverse Event Reporting for Phase 1 Studies 
(Regardless of Expectedness)
Attribution
Grade 1
Grade 2
Grade 3
Grade 4
Unrelated
X
X
X
X
Unlikely
X
X
X
X
Possible
X
X
X
X
Probable
X
X
X
X
Definite
X
X
X
X
Table 8.
Guidelines for Routine Adverse Event Reporting for Phase 2 Studies 
(Regardless of Expectedness) 
Attribution
Grade 1
Grade 2
Grade 3
Grade 4
Unrelated
X
X
Unlikely
X
X
Possible
X
X
X
X
Probable
X
X
X
X
Definite
X
X
X
X
Routine AEs occurring between the start date of intervention until 30 days after the last 
intervention or until the event has resolved, the study patient is lost to follow up, the start of a 
new treatment, or until the study investigator assesses the event(s) as stable or irreversible, will 
be reported. New information will be reported after it is received.
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9.2
Serious Adverse Events
9.2.1
Definition
A serious adverse event (SAE) is any adverse event (experience) that in the opinion of either the 
investigator or sponsor results in ANY of the following:
•
Death.
•
A life-threatening adverse event (experience). Any AE that places a patient or patients, in the 
view of the Investigator or sponsor, at immediate risk of death from the reaction as it 
occurred. It does NOT include an AE that, had it occurred in a more severe form, might have 
caused death.
•
Inpatient hospitalization or prolongation of existing hospitalization (for > 24 hours).
•
A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions.
•
A congenital anomaly or birth defect.
•
Important Medical Event (IME) that, based upon medical judgment, may jeopardize the 
patient or patient and may require medical or surgical intervention to prevent one of the 
outcomes listed above.
9.2.2
Reporting Serious Adverse Events (Network Sites see Appendix A )
All new SAEs occurring from the date the patient signs the study consent until 30 days after the 
last intervention or a new treatment is started, whichever comes first, will be reported. 
The RPCI SAE Source Form is to be completed with all available information, including a brief 
narrative describing the SAE and any other relevant information. 
SAEs occurring after the 30 day follow-up period that the investigator determines to be possibly, 
probably or definitely related to the study intervention should be reported.
SAEs identified as an Unanticipated Problem by the Investigator must be reported. Please refer 
to Section 9.3.2 for details on reporting Unanticipated Problems.
9.2.3
Follow-Up for Serious Adverse Events
All related SAEs should be followed to their resolution, until the study patient is lost to follow 
up, the start of a new treatment, or until the study investigator assesses the event(s) as stable or 
irreversible. New information will be reported when it is received.
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9.3
Unanticipated Problems
9.3.1
Definition
An Unanticipated Problem (UP) is any incident, experience, or outcome that meets all of the 
following criteria:
•
Unexpected (in terms of nature, severity, or frequency) given:
o
The research procedures that are described in the study-related documents, 
including study deviations, as well as issues related to compromise of patient 
privacy or confidentiality of data.
o
The characteristics of the patient population being studied.
•
Related or possibly related to participation in the research (possibly related means there is a 
reasonable possibility that the incident, experience, or outcome may have been caused by the 
procedures involved in the research).
•
Suggests that the research places patients or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or recognized 
and if in relation to an AE is also deemed Serious per Section 9.2.
9.3.2
Reporting Unanticipated Problems
Unanticipated problem reporting will begin at the time of participant consent. An Unanticipated 
Problem shall be submitted to the CRS Compliance Office as “Reportable New Information” in 
the Click system within 1 business day of becoming aware of the Unanticipated Problem. After 
review, CRS Compliance will submit the UP to the IRB. 
When becoming aware of new information about an Unanticipated Problem, submit the updated 
information to CRS Compliance as “Reportable New Information” in the Click system.
Network Sites, see Appendix (A) for information regarding, Unanticipated Problem  
reporting.
9.4
Investigator Reporting: Notifying the Study Sponsor
Adverse events, both serious and non-serious, and deaths that occur during the patient’s study 
participation (from time of the first dose of tivozanib, written informed consent through 30 days 
after receiving the last dose of tivozanib hydrochloride) will be documented. All subjects 
receiving at least 1 dose of tivozanib hydrochloride, whether completing the treatment period or 
not, should be followed for 30 days after the last dose of tivozanib hydrochloride. New AEs and 
changes in ongoing AEs or those with an unknown outcome must be followed for 30 days after 
the last dose of tivozanib hydrochloride. All SAEs should be monitored until they are resolved or 
are clearly determined to be due to a patient’s stable or chronic condition or intercurrent 
illness(es). The Investigator will determine the seriousness, intensity, and causality of an adverse 
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event associated with the use of the study drug (i.e., events where there is a reasonable 
possibility that the event may have been caused by the study drug).
All SAEs should be recorded on a Medwatch Form 3500A and sent to the FDA (if applicable), to 
AVEO Pharmacovigilance/Drug Safety, to the NCCN, and to the Principal Investigator/ CRS 
Network Coordinators at CRSNetworkCoordinators@RoswellPark.org.
SAE Reporting Contact Information: please submit SAE Reports to Parexel GPPG via email 
(AVEOsafety@parexel.com). If submission via email is not possible or delayed then submission 
via fax (NA +1-781-434-5957) is acceptable.
Pharmacovigilance/Drug Safety
AVEO Pharmaceuticals, Inc
One Broadway, 14th Floor
Cambridge, MA 02142
Fax: 1- 781 434 5957
E-mail: AVEOsafety@parexel.com
SAE Reporting Contact Information
National Comprehensive Cancer Network (NCCN)
Fax: (215)358-7699
9.5
FDA Reporting
This protocol is being conducted under a RPCI, IND and it is the responsibility of the study IND 
holder to report certain AEs or Unanticipated Problems to the FDA.
RPCI’s Compliance Office will report Network Site reports to the FDA. 
The following describes the FDA reporting requirements by timeline for AEs and new safety 
findings that meet the criteria outlined below:
Within 7 Calendar Days
Any adverse event that meets ALL the following criteria:
•
Related or possibly related to the use of the study drug;
•
Unexpected; and
•
Fatal or life-threatening.
Within 15 Calendar Days
Any adverse event that meets ALL the following criteria:
•
Related or possibly related to the use of the study drug;
•
Unexpected; and
•
Serious but not fatal or life-threatening.
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Or meets ANY of the following criteria:
•
A previous adverse event that is not initially deemed reportable but is later found to fit the 
criteria for reporting (report within 15 days from when event was deemed reportable).
•
Any findings from other studies, including epidemiological studies, pooled analysis of 
multiple studies, or other clinical studies conducted with the study drug that suggest a 
significant risk in humans exposed to the drug.
•
Any findings from animal or in vitro testing that suggest a significant risk for human subjects 
including reports of mutagenicity, teratogenicity, or carcinogenicity or reports of significant 
organ toxicity at or near the expected human exposure.
•
Any clinically important increase in the rate of occurrence of a serious, related or possibly 
related adverse event over that listed in the protocol or investigator brochure.
Sponsors are also required to identify in IND safety reports, all previous reports concerning 
similar adverse events and to analyze the significance of the current event in the light of the 
previous reports.
Reporting Process
The principal investigator or designee will complete and submit a FDA Form 3500A for any 
event that meets the above criteria. Forms will be submitted to the CRS Compliance Office via 
email: CRSCompliance@Roswellpark.org. The Compliance office will send the form to the 
Administrator of ORSP.
9.6
Procedures for Reporting Subject Death
Any death experienced by a subject after enrollment through 30 days of receiving the last dose of 
tivozanib hydrochloride, regardless of relationship to study drug, or any death that occurs more 
than 30 days after receiving study drug that is believed to be study drug-related must be promptly 
reported (within 24 hours of the investigator becoming aware of the event) by telephone, telefax, 
or e-mail transmission to AVEO Pharmacovigilance/Drug Safety. Reports of all on-study deaths 
must also be communicated promptly to the FDA (if applicable) and the appropriate Institutional 
Review Board (IRB) and/or reported in accordance with local law and regulations.
9.7
Procedures for Reporting Study Drug Overdose
An overdose of tivozanib hydrochloride should be reported if the dose of tivozanib 
hydrochloride administered is greater than the assigned dose for the subject.
Should a subject experience an overdose during the course of the study (whether symptomatic or 
not, and regardless of seriousness), the Sponsor-Investigator or qualified designee must complete 
a Medwatch Form 3500A to report the overdose to AVEO Pharmacovigilance/Drug Safety 
within 24 hours of first becoming aware of the overdose. Follow-up information on the outcome 
of the overdose should be forwarded to the AVEO Pharmacovigilance/Drug Safety.
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 
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be reported as such. If a SAE occurs in conjunction with the overdose, then the reporting time 
frame for a SAE should be followed.
9.8
Procedures for Reporting Drug Exposure During Pregnancy and Birth Events
All pregnancies, including pregnancies in female partners of male study participants, occurring 
from the date of ICF signature until 45 days following tivozanib hydrochloride administration 
must be documented. If it is confirmed that a study participant has become pregnant while 
participating in this trial, study drug administration will be discontinued immediately. Any 
pregnancy occurring during this study will be reported immediately to AVEO 
Pharmacovigilance/Drug Safety.
The Sponsor-Investigator must actively follow-up, document and report the outcome of any 
pregnancy even if the subject has withdrawn from the study. The Sponsor-Investigator will then 
report follow-up information to AVEO Pharmacovigilance/Drug Safety regarding the course of 
the pregnancy, including perinatal and neonatal outcome. Timelines vary according to the nature 
of the pregnancy outcome:
•
For normal outcomes, AVEO Pharmacovigilance/Drug Safety should be notified within 
45 days from birth/delivery.
•
For abnormal outcomes, the fully completed Medwatch Form 3500A must be sent to 
AVEO Pharmacovigilance/Drug Safety according to the same procedures and timelines 
described for expedited AE reporting.
For questions related to safety reporting, contact: AVEO Pharmacovigilance/Drug Safety.
10 DATA AND SAFETY MONITORING
Phase 1 studies will be reviewed at the scheduled RPCI Phase 1 meetings and the minutes are 
forwarded to the IRB for review.
The RPCI Data and Safety Monitoring Board will assess the progress of the study, the safety 
data, and critical efficacy endpoints. The DSMB will review the study annually and will make 
recommendations that include but not limited to; (a) continuation of the study, (b) modifications 
to the design (c) or termination of the study.
11 STATISTICAL METHODOLOGY
This is a Phase 1b/2 study to assess the safety and efficacy of tivozanib therapy in HCC patients. 
The Phase 1b portion follows a modified 3+3 design (refer to Section 3.3), and provides limited 
toxicity information about tivozanib therapy in this patient population. The Phase 2 portion is a 
two-stage, single arm, unblinded trial allowing for early termination in case of futility. Phase 1b 
patients treated at the recommended Phase 2 dose will be included in the Phase 2 trial.
11.1 Phase 1b
To compensate for the current lack of toxicity information about tivozanib treatment in this 
patient population, the safety cohort begins by enrolling 3 patients at Dose Level 1. Then 
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modified 3 + 3 decision rules are followed to determine the recommended Phase 2 dose. Dose 
decision rules are specified in Section 3.3. A schematic of the Phase 1b design is shown in 
Figure 1. The recommended Phase 2 dose will be considered tolerable if DLT(s) are observed in 
at most 1 of 6 patients completing at least 1 treatment cycles at that dose level.
The Phase 1b design requires between 6 and 18 patients. Available information about tivozanib 
treatment suggests Dose Level 2 will be the recommended Phase 2 dose. Under this scenario, the 
safety cohort will consist of 9 patients. The 6 safety cohort patients treated at the recommended 
Phase 2 dose will be included in Stage 1 of the Phase 2 study.
Phase 1b patients who do not complete at least 80% of the prescribed dose in Cycle 1 for reasons 
other than DLT will be replaced.
11.2 Phase 2
The Phase 2 study proceeds in 2 stages, and allows for early stopping for futility. The primary 
endpoint is the percentage of PFS responders, defined as patients who survive without disease 
progression (per RECIST criteria) for least 24 weeks past enrollment.
Stage 1: Enroll 
 patients, including the safety cohort patients treated at the Phase 2 dose. 
   #
If 9 or fewer PFS responses are observed, the therapy will be deemed ineffective and the study 
will end. Otherwise, the study will proceed to the second stage.
Stage 2: Enroll an additional 
 patients. If 
 or fewer PFS responses are observed 
$   %
&  $'
among the total 
 patients, the therapy will be deemed ineffective; otherwise, it will be 
 ( $  ')
concluded that the therapy is promising. Under the null hypothesis of a 50% PFS rate at 
24 weeks, the probability of stopping early for futility is 50%. Under the alternative of a 70% 
PFS rate, this probability is 3.3%. Patients who die or withdraw from the study prior to the 
24th week will be counted as events. These patients will not be replaced. The nominal 
significance level of this design is 
.
  !*!+
11.3 Sample Size Determination
Between 6 and 18 patients will be enrolled in Phase 1b portion. Six Phase 1b patients treated at 
the recommended Phase 2 dose will be included in the Phase 2 portion of this study. An 
additional 31 patients will be enrolled for the Phase 2 portion of this study, for a total Phase 2 
sample size of 37. This study is expected to accrue 9 patients to the Phase 1b, for a combined 
sample of size 40 (=9+37-6). If 18 patients are enrolled in the Phase 1b, the maximum combined 
sample size is 49 (=18+37-6).
The sample size calculation is based on testing hypotheses concerning the proportion of the 
treated population alive and disease free 24 weeks after enrollment. Let p represent the 
proportion of patients surviving with no evidence of disease progression by RECIST at 24 weeks 
after enrollment. A true progression rate of less than p0 = 0.50 is considered unacceptable and 
evidence of such will deem the treatment not worthy of further study. The null and alternative 
hypotheses to be tested are H0:p = p0 versus H1: p > p0.
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This 2-stage design requires a potential total of 37 patients to achieve approximately 
 power 
  ,
to detect a difference of at least Δ percentage points (p0 versus p0 + Δ). For calculations in this 
study, p0 = 0.50, α = 0.05, 1 - β = 0.80 and Δ = 0.20. With these design parameters, the sample 
size was calculated using the web calculator located at http://cryptnet.net/kepner/.17
11.4 Randomization
This is a nonrandomized study.
11.5 Demographics and Baseline Characteristics
Descriptive statistics and statistical plots will be used to summarize changes in biomarkers levels 
in blood and changes in viral titers. The paired t-test, Wilcoxon signed-rank test, and McNemar’s 
test will be used for within-patient comparisons of changes in biomarker levels across times. The 
repeated measures modelling may be used to explore the effects of exogenous factors 
(i.e., diabetes, hepatitis, cirrhosis, etc.) on the changes in biomarkers and viral titers. The effects 
of biomarkers on clinical benefit rate (CR+PR) will be assessed using logistic regression and the 
effects on time-to-event data (overall survival and progression free survival) will be estimated by 
Cox model.
11.6 Efficacy Analysis
The efficacy sample includes all patients enrolled in the Phase 2 study, plus Phase 1b patients 
treated at the recommended Phase 2 dose.  Patients removed from the study for non-compliance 
will be counted as events in the efficacy analyses.
The primary endpoint will be progression free survival at 24 weeks using standard RECIST 
criteria. All enrolled patients will be included in assessment of the primary endpoint. Time-to-
progression will be descriptively analyzed using standard Kaplan-Meier estimation along with 
the corresponding descriptive statistics and 95% confidence intervals.
Secondary endpoints will include, overall survival, toxicity, clinical benefit rate (CR+ PR+ SD). 
Correlative endpoints will also include AFP response, antiviral effect (if any in those with HBV 
or HCV associated HCC) and exploration for any correlation between drug exposure (assessed 
by steady state PK) and response/ survival and toxicity by quartiles of drug exposure will be 
exploratory.
11.7 Safety Analysis
The safety sample will include all patients exposed to the study drug.
Toxicity frequency will be tabulated by grade across all dose levels and cycles for all patients in 
the safety sample, and for the subset treated at the recommended Phase 2 dose. These tables will 
be produced at 3 time points:
1. At the end of the Phase 1b study.
2. At the Phase 2 interim analysis.
3. At the Phase 2 final analysis.
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11.8 Interim Analysis and Criteria for Early Termination of the Study
No explicit interim analysis is planned for the Phase 1b dose-finding portion of the study. 
However, during this phase, observed toxicities will be monitored and discussed weekly by 
RPCI’s Phase 1 Committee. Potential early termination decisions are inherent in the Phase 1 
study monitoring.
The Phase 2 design includes a formal interim analysis, allowing for early termination if the 
experimental treatment is deemed ineffective. Early termination rules are detailed in 
Section 11.2.
12
CORRELATIVE DATA ANALYSIS
12.1 Pharmacokinetic/Pharmacodynamic Analysis
Using data collected from PK and PD samples, a population PK/PD model will be developed to 
characterize the time course of tivozanib concentrations in relation to target increases in 
VEGF-A and decreases in sVEGFR-2. Subsequently, diagnostic plots will be created to ascertain 
whether a trend exists in VEGF-A and sVEGFR-2 changes, immunological biomarker response, 
viral load and progression free survival (PFS). If trends exists, these endpoints will also be 
included in the PK/PD model. A variety of compartmental population pharmacokinetic structural 
models will be evaluated using a nonlinear mixed effects modeling approach, NONMEM®. The 
physiologic pharmacokinetic models explored will be described by the estimation of mean 
structural model parameters (e.g., plasma volumes of distribution and clearances), the magnitude 
of inter-individual variability (IIV) in these parameters, and the magnitude of residual variability 
(RV). The model for IIV will be assumed that the variance is proportional with respect to the 
typical value of the pharmacokinetic parameter, and the estimates are presented as percent 
coefficients of variation. This analysis will include evaluation of the influence of a limited 
number of patient covariates, such as patient demographics along with other patient cofactors, on 
the variability in select PK/PD parameters. Based on our sparse sampling approach, prior 
information on PK parameter estimates and variances can be used with a Bayesian estimation 
method to drive the model analysis. This allows for a smaller number of samples to be taken 
while still providing enough information to achieve sufficient model fitting. For each model, the 
fit will be assessed by examination of several diagnostics. For comparisons of hierarchical 
models, the change in the minimum value of the objective function (MVOF), a statistic that is 
proportional to minus twice the log likelihood of the data, will be examined. This change 
represents a statistic which is asymptotically distributed like χ2, with degrees of freedom equal to 
the number of parameters added to or deleted from the model. For example, a change in the 
MVOF of ≥ 7.88 between two hierarchical models represents a statistically significant difference 
at an α-level of 0.005 for the addition of one parameter (df = 1). The goodness-of-fit of 
NONMEM® analyses will be additionally assessed by examination of the following: 
(1) scatterplots of measured concentrations and weighted residuals versus population predicted 
concentrations, and weighted residuals versus time since first and last dose; (2) scatterplots of 
measured concentrations, individual weighted residuals, and absolute individual weighted 
residuals versus individual predicted concentrations; (3) the precisions of the parameter estimates 
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as measured by the percent standard error of the mean (%SEM = standard error/parameter 
estimate x 100% ); (4) changes in the estimates of interindividual (IIV) and residual variability 
(RV); and (5) histograms, boxplots, and plots of quantiles of individual and population weighted 
residuals versus quantiles of the normal distribution (QQ plots).
12.2 Immune Biomarker
Interest is in the effect of tivozanib on several tumor-associated immune response markers. One 
pre- and two post-treatment measurements will be obtained from each tivozanib-treated patient 
who completes at least two treatment cycles. Post-treatment measurements will be obtained at 
Day 56, and at the end of follow up (either documented disease progression, death or one year of 
progression-free survival). These immune marker measurements will be presented as continuous 
variables.
Primary interest is in the change in immune system measurements obtained at baseline and the 
end of Cycle 2 (Day 56). Using (linear) mixed model methods, the change in expression 
measurement outcomes will be modeled against a random patient effect, and fixed-effects for 
time (pre vs post), patient status at Day 56 (progression/death or not) and the status-by-time 
interaction. Fixed effects for other exogenous effects (e.g. presence of hepatitis B/C, cirrhosis, 
diabetes, etc) may also be included. Mixed model methods account for the hierarchical (within 
patient) covariance in the outcome measurements, and missing outcome observations for patients 
who die/withdraw before finishing Cycle 2.
The magnitude, direction and reliability of the change estimate will be described using the fitted 
parameter estimate for time and its 95% confidence limits. If the immune measurements change 
estimate, depends on the patient status (i.e., if the status-by-time interaction is statistically 
significant), the change will be estimated and tested within progression strata using contrast 
statements.
For power calculations, we assume paired (pre/post) standardized observations are available for 
37 patients, and significance threshold of 0.05. If the change in immune measurements does not 
depend on progression status, then this experiment can be considered as a paired t-test. This test 
has 80% power to detect a 0.47 standard deviation shift in mean immune measurement.
If the change in immune measurements depends on progression status, we further assume a 
within-patient correlation coefficient of 0.2. This ANCOVA-type model combination gives 80% 
power to detect a 1.6 standard deviation difference in the progression strata specific regression 
line slopes.
Appropriate functional forms for the mean function will be explored using means by time box 
plots, scatter plots, and other methods. Within-patient and time correlations will be explored 
using profile plots. Compliance with modeling assumptions will be assessed by examination of 
residual plots. PRESS residuals will be utilized to identify possible influential observations. The 
marker measurements may be transformed to satisfy distributional assumptions. Correlations 
between marker values will be tested using Spearman Rank correlation methods, and visualized 
using spline-augmented scatter plots.
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In all, we expect a total of 8 immune measurements for each patient at each time point (four 
marker measurements, and four phosphorylation measurements). Methods proposed by 
Hochberg will be used to control the overall (family-wise) Type I error rate to 0.05.
In exploratory analyses, the three expression measurement outcomes for each patient will be 
modeled using (linear) mixed model methods with fixed-effects for time, cumulative dose, 
patient status (progressed, died, other), exogenous factors and the second order interactions with 
patient status. The effects of baseline expression measures on progression free and overall 
survival will be assessed using multivariable proportional hazards models, with adjustment for 
possible confounding factors. Survival distributions will be obtained using the product-limit 
based Kaplan Meier methods, with descriptive quantities such as median survival time and 
corresponding 95% confidence intervals.
13 ETHICAL AND REGULATORY STANDARDS
13.1 Ethical Principles
This study will not be initiated until the protocol and informed consent document(s) have been 
reviewed and approved by a properly constituted Institutional Review Board (IRB) or 
Independent Ethics Committee (IEC). Each subject (or legal guardian) shall read, understand, 
and sign an instrument of informed consent prior to performance of any study-specific 
procedure. It is the responsibility of the investigator to ensure that the subject is made aware of 
the investigational nature of the treatment and that informed consent is given.
The Investigator is responsible for the retention of the subject log and subject records; although 
personal information may be reviewed by authorized persons, that information will be treated as 
strictly confidential and will not be made publicly available. The investigator is also responsible 
for obtaining subject authorization to access medical records and other applicable study specific 
information according to Health Insurance Portability and Accountability Act regulations (where 
applicable).
This study will be conducted in compliance with all applicable laws and regulations of the state 
and/or country and institution where the subject is treated. The clinical trial should be conducted 
in accordance with the ethical principles embodied in the Belmont Report: Ethical Principles and 
Guidelines for the Protection of Human Subjects of Research, consistent with good clinical 
practice and the applicable regulatory requirements and according to the guidelines in this 
protocol, including attached appendices.
13.2 Informed Consent
The Investigator (or IRB specified designee) is responsible for obtaining written consent from 
each subject or the subject's legally authorized representative in accordance with GCP guidelines 
using the approved informed consent form, before any study specific procedures (including 
screening procedures) are performed. The informed consent form acknowledges all information 
that must be given to the subject according to applicable GCP guidelines, including the purpose 
and nature of the study, the expected efficacy and possible side effects of the treatment(s), and 
specifying that refusal to participate will not influence further options for therapy. Any additional 
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information that is applicable to the study must also be included. Additional national or 
institutionally mandated requirements for informed consent must also be adhered to. The subject 
should also be made aware that by signing the consent form, processing of sensitive clinical trial 
data and transfer to other countries for further processing is allowed.
The Investigator shall provide a copy of the information sheet and of the signed consent form to 
the subject and the signed original shall be maintained in the Investigator File. A copy of the 
signed consent form must be filed in the subject file. At any stage, the subject may withdraw 
from the study and such a decision will not affect any further treatment options.
14 STUDY RESPONSIBILITIES
14.1 Data Collection
Data entry into the database is to be completed in a timely fashion (within 30 days) after the 
subject’s clinic visit. If an AE is considered serious it is captured on both the Adverse Event page 
and the Serious Adverse Event Form, which is handled in an expedited fashion.
Data management activities will be performed using EXPeRT. EXPeRT is a suite of software 
tools that enables the collection, cleaning and viewing of clinical trial data. CRS data 
management will design the study-specific database and facilitate its development by the 
EXPeRT Information Technology team. Once the database design is approved by the 
Investigator, Statistician, and Clinical Research Coordinator, the database will be put into 
production and data entry can begin. Data can be entered and changed only by those with the 
rights to do so into the eCRFs. EXPeRT is compliant with all relevant technical aspects of 
relevant GCP guidelines.
•
The system can generate accurate copies of stored data and audit trail information in human 
readable form.
•
System access is limited to authorized individuals through the controlled assignment of 
unique ID and password combinations.
•
The system is designed to periodically force users to change their passwords and verifies that 
user ID and password combinations remain unique.
•
The system automatically generates a permanent time-stamped audit trail of all user 
interactions.
When data entry is complete, data management will review the data and will query any missing, 
incomplete, or invalid data points for resolution by the Clinical Research Coordinator and 
Investigator. Once all queries have been resolved, the data can be released to the statistician for 
analysis.
14.2 Maintenance of Study Documents
Essential documents will be retained per RPCI’s policy for 6 years from the study termination 
date. These documents could be retained for a longer period, however, if required by the 
applicable local regulatory requirements or by an agreement with RPCI. 
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15 ADMINISTRATIVE RULES
15.1 Revisions to the Protocol
RPCI may make such changes to the protocol as it deems necessary for safety reasons or as may 
be required by the U.S. FDA or other regulatory agencies. Revisions will be submitted to the 
IRB/ERC for written approval before implementation.
15.2 Termination of the Study
It is agreed that, for reasonable cause, either the RPCI Investigators or the Sponsor, may 
terminate this study, provided a written notice is submitted within the time period provided for in 
the Clinical Trial Agreement. In addition, RPCI may terminate the study at any time upon 
immediate notice if it believes termination is necessary for the safety of subjects enrolled in the 
study.
15.3 Confidentiality
Any data, specimens, forms, reports, video recordings, and other records that leave the site will 
be identified only by a participant identification number (Participant ID, PID) to maintain 
confidentiality. All records will be kept in a limited access environment. All computer entry and 
networking programs will be done using PIDs only. Information will not be released without 
written authorization of the participant.
15.4 Compliance with Laws and Regulations
This study will be conducted in accordance with current US Food and Drug Administration 
(FDA) Good Clinical Practices (GCPs) and local ethical and legal requirements.
15.5 Record Retention
Retain all documentation of adverse events, records of study drug receipt and dispensation, and 
all IRB correspondence for at least 6 years after the investigation is completed.
15.6 Publication Statement
The results of this study will be used for papers, abstracts, posters, or other informational 
materials to be presented at scientific meetings or published in professional journals, or as part of 
an academic thesis by an Investigator. Publications by the clinical trial site (s) of any data from 
this study will be carried out in accordance with the Clinical Trial Agreement.
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16 APPENDICES
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Appendix A. Network Sites
1. CONTACT INFORMATION
All questions related to the protocol or study implementation should be directed to:
Roswell Park Cancer Institute
CRS Network Office
ASB K 104
Buffalo, New York 14263
Telephone:
Monday - Friday; 8:00 AM to 4:30 PM EST
716-845-3155; 716-845-8360
After hours, weekends, and holidays request the RPCI Investigator
716-845-2300; Fax: 716-845-8743
2. INFORMED CONSENT
•
Informed consent must be obtained by the site Investigator/designee from any subjects 
wishing to participate, prior to any procedures or change in treatment.
•
An informed consent template is provided by RPCI and can be amended to reflect 
institutional requirements.
•
All consent changes must be reviewed by RPCI Network Office prior to submission to 
the site IRB.
•
The informed consent must be IRB approved.
•
Always check that the most up to date version of the IRB approved consent is being used.
•
Within 5 business days, notify the RPCI Network Office of all participant withdrawals or 
consent to limited study participation and appropriately document the discontinuation and 
the reason(s) why.
3. SUBJECT REGISTRATION
The subject completes the Gender, Race, and Ethnicity Form and this is placed in the study 
binder.
RPCI does not grant exceptions to eligibility criteria.
Phase 2 Protocol Registration Instructions
The Subject Screening and Enrollment Log must be faxed or emailed to the RPCI Network 
Office within  one business day of the date the subject is consented. Once the Investigator has 
determined that eligibility has been met, complete the  Subject Registration Form and fax or 
email it to the RPCI Network Monitor at 716-845-8743.


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4. STUDY DEVIATIONS
•
If a deviation has occurred to eliminate hazard, this must be reported to the RPCI 
Network, site IRB and any other regulatory authority involved in the trial.
•
ALL study deviation will be recorded on the Study Deviation Log.
•
Notify the RPCI Network Office of any early subject withdrawal and appropriately 
document the discontinuation and the reason why. 
5. STUDY DOCUMENTATION
•
Study documents must be filled out completely and correctly. Ditto marks are not 
allowed.
•
If an entry has been documented in error put a single line through the entry and initial and 
date the change. The RPCI Network Monitor must be able to read what has been deleted.
o
Do NOT use white-out, magic marker, scratch-outs.
o
Do NOT erase entries.
•
Use only black ink for documentation on the accountability form and any other study 
forms.
•
It is the responsibility of RPCI to inform the Investigator/ institution as to when these 
documents no longer need to be retained. If, for any reason, the Investigator desires to no 
longer maintain the study records, they may be transferred to another institution, another 
investigator, or to RPCI upon written agreement between the Investigator and RPCI.
6. DRUG ACCOUNTABILITY
Drug accountability must be strictly maintained.
•
Responsibility rests solely with the Investigator but can be delegated as appropriate 
(e.g., to pharmacy personnel).
•
A drug accountability record form (DARF) will record quantities of study drug received, 
dispensed to subjects and wasted, lot number, date dispensed, subject ID number and 
initials, quantity returned, balance remaining, manufacturer, expiration date, and the 
initials of the person dispensing the medication.
•
Study drug supply will only be used in accordance with the IRB approved study.
•
Drug accountability forms are protocol and agent specific, they are study source 
documents and will be used to verify compliance with the study.
•
An inventory count must be performed with each transaction. Any discrepancies shall be 
documented and explained.
•
Drug accountability forms must be stored with study related documents.
•
Each medication provided for this study and each dosage form and strength must have its 
own DARF.
•
Dispensing the wrong study supply is considered a medication error.
o
NEVER replace investigational agents with commercial product.
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o
Do NOT “transfer”, “borrow” or “replace” supplies between studies.
7. SERIOUS ADVERSE EVENT REPORTING
The site Investigator or designated research personnel will report all SAEs, whether related or 
unrelated to the investigational agent(s) to the IRB in accordance with their local institutional 
guidelines. The site will notify the RPCI Network Monitor within 1 business day of being made 
aware of the SAE. A preliminary written report must follow within 1 business day of the first 
notification using the following forms:
•
RPCI SAE Source report form
•
MedWatch 3500A
•
Drug Supplier is Aveo Pharmaceuticals send to: (please submit SAE Reports to Parexel 
GPPG via email (AVEOsafety@parexel.com). If submission via email is not possible or 
delayed then submission via fax (NA +1-781-434-5957) is acceptable)
Pharmacovigilance/Drug Safety
Aveo Pharmaceuticals, Inc.
One Broadway, 14th Floor
Cambridge, MA 02142Fax: 1-781-434-5957
E-mail: AVEOsafety@parexel.com
•
NCCN National Comprehensive Cancer Network FAX to (215)358-7699
A complete follow-up report must be sent to the RPCI Network Monitor within 10 working days.
8. UNANTICIPATED PROBLEM REPORTING
An unanticipated problem (UP) is any incident, experience, or outcome that meets all of the 
criteria in Section 9.3.1.
For all adverse events occurring that are unanticipated and related or possibly related to the 
research drug, biologic or intervention, the participating physician or delegated research staff 
from each site will notify their local IRB in accordance with their local institutional 
guidelines. The site must also notify the RPCI Network Monitor within 1 business day of being 
made aware of the Unanticipated Problem by completing the RPCI Unanticipated Problem 
Report Form and faxing or emailing it to the RPCI Network Monitor.
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9. ADDITIONAL REQUIRED REPORTING
a.
Refer to protocol Section 9.6 for Procedures for Reporting Subject Death.
b. Refer to protocol Section 9.7 for Procedures for Reporting Study Drug 
Overdose.
c.
Refer to protocol Section 9.8 for Procedures for Reporting Drug Exposure 
during Pregnancy and Birth Events.
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Appendix B. ECOG Performance Status Scores
Description
Status
Fully active, able to carry on all pre-disease performance without restriction.
0
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or 
sedentary nature, e.g., light housework, office work.
1
Ambulatory and capable of all self-care but unable to carry out any work activities.
2
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours.
3
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair.
4
Dead
5
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Appendix C. Recommended Management for Tivozanib Hydrochloride-Related 
Hypertension


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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


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Appendix E1.
Patient Pill Diary(Full Dose)
Study No.: ____________________
Patient’s Name: ______________________________
Drug Name: __________________
Cycle:______________________
Medical Record No.: ___________
Study Medication Calendar for Tivozanib
You should swallow your medication, unchewed, with a large glass of water (about 8 oz.) in the morning every day with or 
without food. On days of a scheduled clinic visit, you should take your dose at the clinic after visit procedures are completed. If a 
dose is vomited or if you miss your dose for any reason, the dose should not be made up.
Please complete this calendar on a daily basis immediately after you take your pills. Fill in the date for each day and write the 
total number of pills you take each day.
Start Date: _________________
Take 1 pill each time.
Cycle Day
Day 1**
Day 2
Day 3
Day 4
Day 5
Day 6
Day 7
Time
Date
Number of 
pills taken
Cycle Day
Day 8
Day 9
Day 10
Day 11
Day 12
Day 13
Day 14
Time
Date
Number of 
pills taken
Cycle Day
Day 15
Day 16
Day 17
Day 18
Day 19
Day 20
Day 21
Time
Date
Number of 
pills taken
Cycle Day
Day 22
Day 23
Day 24
Day 25
Day 26
Day 27
Day 28
Date
Number of 
pills taken
No medication is to be taken during this time.
**Do NOT take your pill on Day 1 until your blood is drawn and the study staff instructs you to take it.
Please remember to bring this calendar and your pill bottle (including any unused pills) with you to your next clinic 
appointment.
Coordinator’s Use Only
	
 

		
  
		

		h	
   !!
"""""	
  
  

   !!
Patient’s Signature:__________________________________________
Date:____________
CRC Signature:_____________________________________________
Date:____________
Investigator Signature:_______________________________________
Date:___________
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Appendix F2.
Patient Pill Diary(Dose Reduced)
Study No.: ____________________
Patient’s Name: ______________________________
Drug Name: __________________
Cycle:______________________
Medical Record No.: ___________
Study Medication Calendar for Tivozanib
You should swallow your medication, unchewed, with a large glass of water (about 8 oz.) in the morning every day with or 
without food. On days of a scheduled clinic visit, you should take your dose at the clinic after visit procedures are completed. If a 
dose is vomited or if you miss your dose for any reason, the dose should not be made up.
Please complete this calendar on a daily basis immediately after you take your pills. Fill in the date for each day and write the 
total number of pills you take each day.
Start Date: _________________
Take 1 pill each time.
Cycle Day
Day 1**(dose1)
Day 2
Day3(dose2)
Day 4
Day5(dose3)
Day 6
Day7(dose4)
Time
Date
Number of 
pills taken
Cycle Day
Day 8
Day 9(dose5)
Day 10
Day11(dose6)
Day 12
Day13(dose7)
Day 14
Time
Date
Number of 
pills taken
Cycle Day
Day15(dose8)
Day 16
Day17(dose9)
Day 18
Day19(dose10)
Day 20
Day 21
Time
Date
Number of 
pills taken
Cycle Day
Day 22
Day 23
Day 24
Day 25
Day 26
Day 27
Day 28
Date
Number of 
pills taken
No medication is to be taken during this time.
**Do NOT take your pill on Day 1 until your blood is drawn and the study staff instructs you to take it.
Please remember to bring this calendar and your pill bottle (including any unused pills) with you to your next clinic 
appointment.
Coordinator’s Use Only
	
 

		
  
		

		h	
   !!
"""""	
  
  

   !!
Patient’s Signature:__________________________________________
Date:____________
CRC Signature:_____________________________________________
Date:____________
Investigator Signature:_______________________________________
Date:___________
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Appendix G. Separation of PBMC on FICOLL Hypaque Gradient
1. Collect peripheral blood in heparinized green top tubes (BD vacutainerR Sodium Heparin, 
REF 366480). Process blood immediately as detailed below.
1.1.
Dilute 40 mL of blood with equal volume of 1 x sterile PBS (Cellgror, Mediatech, 
Inc. Cat. No. 2 appent1.031-CV) and mix gently using sterile pipette (Do not vortex).
1.2.
Put 15 mL of Ficoll (Ficoll-PaqueTM Plus, GE Healthcare, 17-1440-42) into a 50 mL 
sterile centrifuge tube (CorningR 430828, Corning Incorporated).
1.3.
Using a sterile pipette, gently layer 30 mL of the diluted blood over 15 mL Ficoll in 
50 mL sterile centrifuge tube, without disturbing the Ficoll layer.
1.4.
Centrifuge the tubes at settings of 2500 rpm, room temperature for 15 minutes, 
centrifuge break must be off.
1.5.
After centrifugation aspirate 8 mL of diluted plasma without disturbing the 
mononuclear cell layer and transfer to 2 polypropylene tubes (4 mL each) and freeze 
the tubes at –80˚C.
1.6.
After the removal of plasma, carefully transfer the mononuclear cell layer (ring), 
using a sterile pipette into one 50 mL sterile centrifuge tube containing 10 mL: PBS. 
Top up the tube to 50 mL with PBS.
1.7.
Gently invert the tube containing mononuclear cells few times to mix, and centrifuge 
the tubes at 1,500 rpm, room temperature for 5 minutes.
1.8.
After the centrifugation step, carefully remove the supernatant and discard and gently 
resuspend each cell pellet in 2 mL of PBS and combine the cell suspensions from all 
centrifuge tubes into a single tube. Dilute cell suspension to 50 mL with PBS, invert 
tube gently to mix, and centrifuge at 1500 rpm, room temperature for 5 minutes.
1.9.
After centrifugation remove the supernatant and gently resuspend the cell pellet in 
10 mL PBS. Mix the cells by gently inverting the tubes. Remove 100 μL sample for 
cell count and viability. Dilute the cells appropriately, so that you are able to count a 
minimum 75 cells to maximum 100 cells.
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1.10.
Count the cells in a Hemocytometer (Neubauer) after mixing with equal volume 0.4% 
Trypan blue stain in PBS. Count all cells in the four large corner squares as shown 
below.
Cell Counts
Squares
1
2
3
4
Average 
Cell Count
(1+2+3+4)/4
Final Cell 
Concentration
Total
PBMC
Viable
Percentage of viable cells = Average viable cells / Average total cells x 100
Cell concentration = Average cell count x 104 x dilution factor ___________________
Total amount of cells = Cells/mL x volume (10 mL) ___________________
2. Cryopreservation of PBMC in Freezing Medium
2.1.
Preparation of freezing medium. Prepare appropriate volume of freezing medium 
based on the total number of PBCs to be frozen.
2.2.
Thaw frozen tube of heat inactivated human AB (HAB) serum (CellgroR, Mediatech, 
Inc. Cat. No. 35-060-CL) in a 37˚C water bath.
2.3.
Add one part of DMSO (Sigma Cat. No. D5879) to 9 parts of heat inactivated HAB 
serum (90% HAB serum+10% DMSO) and mix well.
2.4.
Centrifuge the PBMC at 1500 rpm for 5 minutes, decant the supernatant and gently 
resuspend the pellet in freezing medium at a concentration of 107 cells/mL of freezing 
medium.
2.5.
Dispense 1 mL of the cell suspension into cryovials and keep overnight in -80˚C. 
Next day transfer the vials to liquid nitrogen.
4
3
2
1
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3. Preservation of Cells in RNA Later
3.1.
Take a volume of cell suspension (equivalent to 4 x 106 cells) in a 50 mL centrifuge 
tube.
3.2.
Centrifuge at 1500 rpm for 5 minutes, decant the supernatant, and gently resuspend 
the cells in 1 mL PBS.
3.3.
Pipette out 0.5 mL of cell suspension into each of 2 sterile eppendorf  tubes 
containing 1 mL of RNA later (Ambion Cat. No. AM7021) and mix well before 
freezing the tubes at -20˚C overnight and then transfer to -80˚C.
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Appendix H. Child-Pugh liver function Class A
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Appendix I.
Procedure for Obtaining a Urine Protein /Creatinine Ratio
1) Obtain at least 4 ml of a random urine sample (does not have to be a 24-hour urine)
2) Determine protein concentration (mg/dL)
3) Determine creatinine concentration (mg/dL)
4) Divide #2 by #3 above: urine protein / creatinine ratio = protein concentration (mg /dL) /
Creatinine concentration (mg/dL)
The UPC directly correlates with the amount of protein excreted in the urine per 24 hrs (i.e. a 
UPC of I should be equivalent to 1 g protein in a 24hr urine collection)
Protein and creatinine concentrations should be available on standard reports of urinalyses, not
dipsticks. If protein and creatinine concentrations are not routinely reported at an Institution, 
their measurements and reports may need to be requested.
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17
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