Conditions: Recurrent Epithelial Ovarian Cancer Recurrent Fallopian Tube Cancer Recurrent Primary Peritoneal Cancer
Keywords: Cancer Recurrent Ovary Fallopian Tube Primary Peritioneal Phase II Platinum Resistant
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 31
Healthy volunteers: no

Brief summary:
This phase II trial studies how well tivozanib works in treating patients with recurrent ovarian, fallopian tube, or primary peritoneal cancer. Tivozanib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Detailed description:
PRIMARY OBJECTIVES:

I. To determine the clinical activity of tivozanib in patients with platinum-resistant, recurrent ovarian, fallopian tube or primary peritoneal cancer.

SECONDARY OBJECTIVES:

I. Determining the potential survival advantage and characterizing the safety of single agent tivozanib in patients with platinum-resistant ovarian cancer.

OUTLINE:

Patients receive tivozanib hydrochloride orally (PO) once daily (QD) on days 1-21. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 2 years and then every 6 months for 3 years.

Arms:
arm 1: Tivozanib 1.5mg orally given daily for 3 weeks with one week off to complete a 4 week cycle until disease progression or adverse effects prohibit further therapy

Interventions: intervention 1: Tivozanib
Intervention descriptions: intervention 1: 1.5 mg Given PO (orally)days 1-21 or every 28 day cycle

Protocol document:
Prot_SAP_000.pdf: 
Northwestern University 
 
                        
Study Number: NU12G11 
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Initial Version Date: 04/28/2013 
 
 
Amendment 8: 1/3/2019 
 
 
 
The Efficacy and Safety of Tivozanib in Recurrent, Platinum-
Resistant Ovarian, Fallopian Tube or Primary Peritoneal Cancer 
 
Principal Investigator: 
Daniela Matei, MD 
Northwestern University Feinberg School of Medicine 
303 E. Superior St, Suite 04-107 
Chicago, Il 60611 
Phone: 312.472.4684 
Email: daniela.matei@northwestern.edu 
 
Sub-Investigators: 
John R. Lurain, MD 
 
Wilberto Nieves-Neira, MD 
 
Shohreh Shahabi, MD 
Anna Strohl, MD 
Emma Barber, MD, MS 
 
Valerie Nelson, MD 
 
Alok Pant, MD 
 
Division of Gynecologic Oncology, Northwestern University 
 
 
Barbara Buttin, MD 
 
LaToya Perry, MD 
 
Division of Gynecologic Oncology 
CDH-Delnor Health System 
Northwestern Medicine Cancer Center  
4405 Weaver Parkway 
Warrenville, IL 60555 
And 
304 Randall Road 
Geneva, IL 60134 
 
Biostatistician: 
     Masha Kocherginsky, PhD 
 
mkocherg@northwestern.edu  
 
 
Study Intervention(s): 
Tivozanib Hydrochloride 
 
IND Number: 
117703 
 
IND Holder: 
Daniela Matei, MD 
 
Funding Source:  
National Comprehensive Cancer Network (NCCN) 
 
Version Date: 
January 3, 2019 
 
Coordinating Center:  
Northwestern University 
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Department of Obstetrics & Gynecology 
 
Division of Gynecologic Oncology 
250 E. Superior St., Suite 05-2168 
 
Chicago, IL 60611 
 
 
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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ......................................................................................................... 5 
STUDY SCHEMA.......................................................................................................................... 6 
STUDY SUMMARY...................................................................................................................... 7 
1 
INTRODUCTION - BACKGROUND & RATIONALE ....................................................... 8 
1.1 
Disease Background-Ovarian Cancer .............................................................................. 8 
1.2 
Tivozanib Hydrochloride ................................................................................................. 8 
1.3 
Study Rationale .............................................................................................................. 17 
2 
STUDY OBJECTIVES ......................................................................................................... 18 
2.1 
Primary ........................................................................................................................... 18 
2.2 
Secondary ....................................................................................................................... 18 
2.3 
Exploratory ..................................................................................................................... 19 
3 
PATIENT SELECTION ....................................................................................................... 19 
3.1 
Inclusion Criteria ............................................................................................................ 19 
3.2 
Exclusion Criteria ........................................................................................................... 21 
4 
TREATMENT PLAN ........................................................................................................... 23 
4.1 
Overview ........................................................................................................................ 23 
4.2 
Study Drug Administration: Tivozanib .......................................................................... 24 
4.3 
General Concomitant Medication and Supportive Care Guidelines .............................. 24 
4.4 
Duration of Therapy ....................................................................................................... 26 
4.5 
Duration of Follow Up ................................................................................................... 26 
4.6 
Removal of Subjects from Study Treatment and/or Study as a Whole .......................... 26 
4.7 
Dose Delays/Dose Modification .................................................................................... 27 
5 
RESPONSE ASSESSMENT ................................................................................................ 28 
5.1 
Antitumor Effect – Solid Tumors................................................................................... 29 
5.2 
Disease Parameters ......................................................................................................... 29 
5.3 
Methods for Evaluation of Measurable Disease ............................................................ 30 
5.4 
Response Criteria ........................................................................................................... 32 
5.5 
Duration of Response ..................................................................................................... 33 
5.6 
Progression-Free Survival .............................................................................................. 34 
5.7 
Survival .......................................................................................................................... 34 
6 
DRUG INFORMATION ...................................................................................................... 34 
6.1 
Tivozanib Hydrochloride ............................................................................................... 34 
7 
CLINICAL AND LABORATORY EVALUATIONS ......................................................... 36 
7.1 
Schedule of Assessments ............................................................................................... 36 
8 
STATISTICAL METHODS ................................................................................................. 38 
9 
ADVERSE EVENTS ............................................................................................................ 39 
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9.1 
Adverse Event Monitoring ............................................................................................. 39 
9.2 
Definitions & Descriptions............................................................................................. 39 
9.3 
Adverse Event Reporting ............................................................................................... 41 
9.4 
IND Annual Reports....................................................................................................... 44 
10 CORRELATIVES/SPECIAL STUDIES .............................................................................. 44 
10.1 
Sample Collection Guidelines .................................................................................... 44 
10.3 
Assay Methodology .................................................................................................... 45 
11 STUDY MANAGEMENT ................................................................................................... 45 
11.1 
Institutional Review Board (IRB) Approval and Consent .......................................... 45 
11.2 
Amendments ............................................................................................................... 45 
11.3 
Registration Procedures .............................................................................................. 46 
11.4 
Data Submission ......................................................................................................... 46 
11.5 
Instructions for Participating Sites ............................................................................. 46 
11.6 
Data Management and Monitoring/Auditing ............................................................. 47 
11.7 
Adherence to the Protocol .......................................................................................... 47 
11.8 
Investigator Obligations ............................................................................................. 48 
11.9 
Publication Policy ....................................................................................................... 48 
12 APPENDICES ...................................................................................................................... 51 
12.1 
Appendix A Performance Status Criteria ................................................................... 51 
12.2 
Appendix B Cytochrome P450 (CYP3A4) Strong/moderate Inducers/Inhibitors ..... 52 
12.3 
Appendix C: Management of Hypertension ............................................................... 53 
12.4 
Appendix D CTCAE v.4.03 ....................................................................................... 55 
12.5 
Appendix E: Summary of Changes ............................................................................ 56 
 
 
 
 
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LIST OF ABBREVIATIONS 
 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
ALC 
Absolute Lymphocyte Count 
AST 
Aspartate Aminotransferase 
BUN 
Blood Urea Nitrogen 
CBC 
Complete Blood Count 
CMP 
Comprehensive Metabolic Panel 
CR 
Complete Response 
CT 
Computed Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLT 
Dose Limiting Toxicity 
DSMB 
Data and Safety Monitoring Board 
ECOG 
Eastern Cooperative Oncology Group 
H&PE 
History & Physical Exam 
HUVECs 
Human Umbilical Vein Endothelial Cells 
IV (or iv) 
Intravenously 
MTD 
Maximum Tolerated Dose 
NCI 
National Cancer Institute 
ORR 
Overall Response Rate or Objective Response Rate 
OS 
Overall Survival 
PBMCs 
Peripheral Blood Mononuclear Cells 
PD 
Progressive Disease 
PFS 
Progression Free Survival 
PO (or p.o.) 
Per os/by mouth/orally 
PR 
Partial Response 
SAE 
Serious Adverse Event 
SD 
Stable Disease 
SGOT 
Serum Glutamic Oxaloacetic Transaminase 
SPGT 
Serum Glutamic Pyruvic Transaminase 
VEGF 
Vascular Endothelial Growth Factor 
WBC 
White Blood Cells 
 
 
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STUDY SCHEMA 
 
 
 
Screening/Eligibility: 
Patients with recurrent or persistent, platinum resistant epithelial ovarian, 
fallopian tube or primary peritoneal carcinoma 
Treatment (28 days per cycle): 
Tivozanib 1.5 mg PO once daily for 21 
days (3 weeks on/ 1 week off). 
Disease Assessment: 
Evaluation after every 2 cycles (CT or 
MRI) 
Continue treatment until: 
• Disease Progression 
• Unacceptable Toxicity 
• Patient Preference 
• Physician recommendation 
Follow Up: 
Follow every 3 months for study related 
toxicities and survival 
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STUDY SUMMARY 
 
Title 
The Efficacy and Safety of Tivozanib in Recurrent, Platinum-Resistant 
Ovarian, Fallopian Tube or Primary Peritoneal Cancer 
 
Protocol Date 
Revised January 3, 2019 (Amendment 8) 
Study Duration 
24 Months 
Study Center(s) 
Robert H. Lurie Comprehensive Cancer Center at Northwestern 
University  
Objectives 
Primary: The primary objective of this single-arm, phase II clinical trial 
will be to determine the clinical activity of tivozanib in patients with 
platinum-resistant, recurrent ovarian, fallopian tube or primary 
peritoneal cancer.   
 
Secondary:  To determine the potential survival advantage and 
characterizing the safety of single agent tivozanib in patients with 
platinum-resistant ovarian cancer. 
Number of Subjects 
30 
Diagnosis and Key 
Eligibility Criteria 
Women with measurable and non-measurable recurrent or persistent, 
platinum resistant epithelial ovarian, fallopian tube or primary 
peritoneal carcinoma. 
Treatment Plan 
Tivozanib 1.5mg orally given daily for 3 weeks with one week off to 
complete a 4 week cycle until disease progression or adverse effects 
prohibit further therapy. 
Statistical 
Methodology 
Statistical analyses will focus on estimation of overall response rates in 
patients with platinum-resistant ovarian cancer as stated in the Primary 
Objective. For the secondary objective, the Kaplan-Meier method will 
be utilized to estimate the median and overall distribution of 
progression-free survival.  Toxicity will also be evaluated as a 
secondary objective and grades will be summarized by counts and 
frequencies. 
 
 
 
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1 
INTRODUCTION - BACKGROUND & RATIONALE 
1.1 
Disease Background-Ovarian Cancer 
Ovarian cancer is the leading cause of gynecologic cancer deaths, and the fifth most 
common cause of cancer deaths in women [1].  Although about 75% of patients with 
epithelial ovarian cancer will respond to first-line chemotherapy with 
carboplatin/cisplatin and paclitaxel, most patients with advanced stage epithelial ovarian 
cancer will recur. While there are several active cytotoxic agents for the treatment of 
recurrent epithelial ovarian cancer, median survival after recurrence is about 2 years.  
Patients who recur more than 6 months after completing their adjuvant chemotherapy are 
referred to as “platinum-sensitive.”  They are oftentimes re-treated with a platinum agent, 
sometimes in combination with additional chemotherapy and, generally speaking, have a 
durable response to subsequent therapy.  Women who recur within 6 months of 
completing adjuvant therapy are referred to as “platinum-resistant.”  These patients 
represent an unfortunate sub-group.  There are multiple agents with clinical activity in 
this setting but the ideal treatment modality is not known.  A recent Cochrane review 
identified topotecan, pegylated liposomal doxorubicin and paclitaxel as having the 
greatest potential benefit for these patients.  The overall response rate for these agents 
ranges from 10-15% in platinum-resistant disease.  The choice of treatment is often based 
on the side-effect profile and the patient’s specific situation [2].  Given these poor 
response rates, new treatment options are needed in this patient population. 
 
1.2 
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 is a novel and potent pan-
vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitor with 
significant activity against all 3 VEGF receptors (VEGFR-1, -2, and -3) [3]. In 
nonclinical models and studies performed in humans, tivozanib 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 inhibits angiogenesis and vascular permeability in 
tumor tissues, leading indirectly to inhibition of tumor growth [4]. 
 
 Non-clinical Studies 
Tivozanib hydrochloride potently and selectively inhibited VEGF ligand-induced 
VEGFR-1, 2, 3 phosphorylation and proliferation of human umbilical vein 
endothelial cells (HUVECs). In nonclinical studies, oral tivozanib hydrochloride 
was highly bioavailable (70%-80%). Daily oral administration of tivozanib 
hydrochloride demonstrated antitumor effects against a broad panel of tumor 
types subcutaneously engrafted into nude mice or rats. The minimum effective 
dose in rats was 0.2 mg/kg/day; average blood levels of tivozanib (free base) 
during continuous dosing at 0.2 mg/kg/day were estimated to be 70ng/mL. At 
these dose levels, the antitumor effects in nude rat xenograft models correlated 
with inhibition of tumor angiogenesis and vascular permeability. Conversely, the 
inhibitory activity of tivozanib hydrochloride in vitro against the growth of 
various cancer cells was weak (IC50 > 1), suggesting that the anti-tumor effect of 
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tivozanib hydrochloride in vivo is not attributable to cytotoxicity or direct 
inhibition of the growth of tumor cells. This suggests that, by inhibiting VEGF-
induced VEGFR activation, tivozanib hydrochloride inhibits angiogenesis and 
vascular permeability in tumor tissues, and such inhibition leads to an indirect but 
broad spectrum of inhibition of tumor growth. Neither long-term therapy nor 
intermittent dosing resulted in any detectable drug resistance in xenograft models. 
All safety pharmacology evaluations were performed after a single oral (gavage) 
administration of tivozanib hydrochloride. There were no significant gross 
behavioral or physiological changes observed in the Irwin test carried out in rats. 
In the monkey telemetry study, 0.015 or 0.3 mg/kg of tivozanib hydrochloride had 
no significant effect on arterial blood pressure (systolic, diastolic or mean), 
however, 3 mg/kg tivozanib hydrochloride increased systolic, diastolic and mean 
arterial blood pressure transiently by as much as 14–19 mmHg. Evaluation of 
electrocardiograms showed that tivozanib hydrochloride had no effects on heart 
rate, respiration rate, PR, QT, or QTc intervals or QRS duration at any of the 
doses tested. Tivozanib hydrochloride produced no inhibition of human ether-a-
go-go (hERG)-related channel tail current in HEK293 cells stably transfected with 
hERG cDNA. Finally, tivozanib hydrochloride had no significant effect on the 
respiration rate or tidal volume of conscious rats at any of the time points or doses 
(0.3–400 mg/kg) tested [5]. 
Nonclinical toxicology studies were conducted in multiples species (rats, mice, 
rabbits and nonhuman primates) to support the safety of tivozanib hydrochloride. 
The investigations included single-dose, repeat-dose (up to 39 weeks), 
genotoxicity, reproductive and developmental toxicity, mechanistic toxicology 
and phototoxicity studies. Toxicities were similar across species and consistent 
with toxicities expected for a drug of this class, namely hypertension, effects on 
growth plate hypertrophy, and renal and gastrointestinal effects. Higher drug 
doses generally caused more profound toxicities, including death, presumably 
attributable to direct pharmacological effects. In general, adverse findings 
resolved or showed signs of ongoing reversal after withdrawal of treatment. For 
all nonclinical studies, tivozanib hydrochloride was used, unless otherwise 
specified. For all oral nonclinical studies, tivozanib hydrochloride was suspended 
in 0.5% methylcellulose vehicle. For IV studies, tivozanib hydrochloride was in a 
40% dimethylacetamide solution. 
Tivozanib hydrochloride demonstrated antitumor effects against a broad spectrum 
of solid tumor models after daily oral administrations. These include human 
tumor xenografts subcutaneously implanted into nude mice and rats, as well as 
genetically engineered murine tumor models bearing specific human oncogenes 
such as mutated KRAS and HER2. 
The pharmacokinetics of tivozanib hydrochloride has been studied in rats and 
monkeys. Following a single oral dose, the time to max serum concentration for 
tivozanib (free base) is 2-4 hours and the half- life is 7-12 hours in both species. 
Systemic exposure was approximately dose-proportional in both species with 
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slight accumulation after multiple doses, consistent with a long half-life relative to 
the dosing interval. The mean bioavailability of tivozanib (free base) in rats is 
71.8% - 82.4%. Following oral administration of [14C]-tivozanib hydrochloride 
to rats, radioactivity was widely distributed throughout the tissues, reaching 
maximum tissue concentrations at four hours post- dosing. Following both oral 
and IV administration in rats, dosed radioactivity was recovered principally in the 
feces. 
Tivozanib hydrochloride has been assayed for protein binding in plasma. The 
proportion of drug that is protein-bound is 97.6%, 99.3%, and 99.7% in monkey, 
rat, and human plasma, respectively. 
In vitro studies have shown that the cytochrome (CYP) P450 enzyme system is 
involved in the metabolism of tivozanib hydrochloride. The primary human 
hepatic isoform shown to be involved in the biotransformation of tivozanib 
hydrochloride was CYP3A4. 
A cardiovascular study in conscious telemetered cynomolgus monkeys did not 
show any effects on QTc interval. In the same study, oral administration of 0.015 
or 0.3 mg/kg tivozanib hydrochloride to cynomolgus monkeys had no effects on 
arterial blood pressure; however, administration of 3.0 mg/kg tivozanib 
hydrochloride increased arterial blood pressure transiently by 14-19 mmHg. 
Tivozanib hydrochloride had no marked effects on heart rate or ECG parameters 
at any tested dose. 
Nonclinical cutaneous and ocular phototoxicity studies indicate that tivozanib 
hydrochloride has no potential phototoxicity [6]. 
 Clinical Studies 
The substantial growth inhibition observed with tivozanib across pre-clinical 
models led to a Phase I study in advanced solid tumors. Key eligibility criteria 
included a life expectancy of at least 3 months and an Eastern Cooperative 
Oncology Group (ECOG) performance status of 0 - 2.  Patients with symptomatic 
brain metastasis were excluded, as were patients with evidence of severe 
cardiovascular disease (i.e., uncontrollable hypertension or symptomatic heart 
failure). A starting dose of 2.0 mg was selected based on the no observed adverse 
effect level (NOAEL) in primates. Extensive pharmacokinetic (PK) sampling was 
performed, and pharmacodynamic  studies were also performed to assess the 
effect of tivozanib therapy on serum VEGF and soluble VEGFR2 (sVEGFR2). A 
total of 41 patients were enrolled into the study. Metastatic colon cancer (n = 10), 
metastatic renal cell cancer (MRCC) (n = 9), and pancreatic cancer (n = 6) 
represented the most common tumor types represented in the study. Two patients 
in the 2.0 mg-daily cohort experienced dose-limiting toxicities (DLTs), 
specifically, grade 3 asymptomatic proteinuria in one patient and grade 3 ataxia in 
another. No DLTs were observed in 6 patients treated at 1.0 mg daily, and 
therefore, an intermediate dose of 1.5 mg daily was explored. DLTs observed at 
this cohort included grade 3 and 4 transaminitis, uncontrollable hypertension, 
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grade 3 fatigue, and grade 3 dyspnea. Given these toxicities, an expansion cohort 
including 12 patients treated at 1.0 mg daily was assessed. With respect to 
efficacy, two patients with mRCC had partial responses (one confirmed, one 
unconfirmed), whereas the majority of patients in the study (55.2%) had stable 
disease as a best response. Eight patients (20%) received therapy for more than 9 
months. PK analyses accompanying the study showed a mean half- life of 4.7 
days (range, 1.3 to 9.7 days). The time to achieve maximum serum concentration 
(tmax) was between 2 and 24 hours. Other correlative studies showed that 
although VEGF-A levels rose consistently at the start of tivozanib therapy in a 
dose-dependent manner, these levels normalized after 14 days off therapy. In 
contrast, sVEGFR2 levels were reduced with increasing doses of tivozanib with 
the most marked decrease noted toward the end of the cycle (i.e., a larger decrease 
was observed at day 27 of therapy versus day 14). Dynamic contrast-enhanced 
MRI (DCE-MRI) was performed in a small subset of patients enrolled in the 
study (n = 8). Consistent with pre-clinical observations, a decrease in tumor 
vessel density was observed over time [7]. 
In the setting of colorectal cancer, a Phase Ib study was conducted to assess the 
activity of tivozanib in combination with 5-flurouracil/oxaliplatin (FOLFOX) 
chemotherapy. A regimen of modified FOLFOX6 (mFOLFOX6), which 
incorporates an 85 mg/m2 dose of oxaliplatin, was administered on days 1 and 15 
of a 28-day cycle. Escalating doses of tivozanib were administered on a 3 weeks 
on, 1 week off cycle. To supplement PK analyses, a single dose of tivozanib was 
given 5 days preceding therapy with tivozanib. A total of 30 patients were 
ultimately enrolled in the study, with a median age of 58 years. In total, 9 patients 
received tivozanib at a dose of 0.5 mg daily, 3 patients received 1.0 mg daily and 
18 patients received 1.5 mg daily. The median duration of treatment was 5.2 
months, and 30.8% of patients achieved a response with this combination. An 
additional 36% of patients had stable disease as a best response. With respect to 
safety, there were four DLTs observed. In dose escalation cohorts, a DLT of 
uncontrolled hypertension was observed. In an expansion cohort including an 
additional 10 patients, three DLTs were observed; specifically, two episodes of 
reversible transaminitis and one episode of uncontrolled hypertension. PK 
analyses from this Phase I experience did not suggest any appreciable interaction 
between mFOLFOX6 and tivozanib ---- levels of tivozanib were akin to those 
observed with monotherapy. The appreciable safety and efficacy associated with 
the combination of mFOLFOX6 and tivozanib have culminated in a larger, 
randomized Phase II effort. In this study, patients will be randomized to receive 
either mFOLFOX6 with tivozanib or bevacizumab. The primary endpoint of the 
study is PFS, with secondary endpoints including OS, response, and health-related 
quality of life (HRQoL). The study also aims to explore a variety of serum 
biomarkers, including VEGF-A, VEGF-C, and VEGF-D and will assess a 42-
gene signature. A second ongoing effort will explore the combination of 
capecitabine and tivozanib in patients with all solid tumor types, but will include 
an expansion cohort in two malignancies ----namely, colorectal cancer and breast 
cancer. The primary objective of the study is to determine the safety of the 
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combination. If a maximally tolerated dose (MTD) is not reached in a general 
population of solid tumor patients, then a recommended Phase II dose will be 
determined and an expansion cohort including breast and colorectal cancer 
patients will be assessed [8]. 
Assessment of tivozanib in breast cancer thus far is limited to a Phase I dose-
finding study in combination with paclitaxel. The primary objective of the study 
was to determine the safety and tolerability of tivozanib in combination with 
paclitaxel in patients with metastatic breast cancer and to evaluate the PK profile 
of this combination. Patients with metastatic breast cancer with an ECOG 
performance status 0 - 2 and < 4 prior lines of therapy were enrolled. Notably, 
patients were allowed to receive one prior taxane and there was no limit to the 
number of prior biologic or endocrinologic treatments, although prior treatment 
with a VEGF-TKI was not allowed. Key exclusion criteria included evidence of 
brain metastasis or pre-existing neuropathy. The treatment regimen included 
weekly paclitaxel (90 mg/m2 intravenous, 3 out of 4 weeks) and escalating doses 
of tivozanib therapy (0.5, 1.0, and 1.5 mg daily). Ultimately, a total of 18 patients 
were included in the study. The median age of the cohort was 48, with 56 and 
22% of patients demonstrating hormone receptor and HER2-positivity. All 
patients had received at least one prior taxane, with 61% of patients having 
received taxane therapy in the adjuvant setting. Notably, over half of patients 
(56%) had received prior bevacizumab. Two dose-limiting toxicities (DLTs) were 
encountered in the study. Namely, one patient treated at the first dose level 
(tivozanib at 0.5 mg/day) experienced grade 1 palpitations while another patient 
treated at the third dose level (tivozanib at 1.5 mg/day) developed grade 2 
asymptomatic pneumoperitoneum. Otherwise, fatigue and alopecia were the most 
commonly reported treatment-emergent adverse events. The median duration of 
tivozanib therapy was 5.4 months. Among the 13 patients evaluable for response, 
partial responses were observed in 5 patients (38%), whereas stable disease was 
observed in 7 patients (54%). Although detailed PK data were not available for 
the patients enrolled, it was suggested that the PK parameters for tivozanib in 
combination with paclitaxel were similar to those associated with tivozanib 
monotherapy [9]. 
A randomized Phase II discontinuation study of tivozanib in mRCC provided key 
insights related to the drug’s activity in this disease. Eligibility in the study was 
limited to mRCC patients with up to one prior therapy (other than a VEGF-
directed agent) and a Karnofsky performance status of >= 70%. Patients were not 
allowed to enroll if they had evidence of brain metastasis or had evidence of 
substantial cardiovascular disease (i.e., uncontrollable hypertension or clinically 
significant heart failure). In accordance with the randomized Phase II design, 
patients received open-label tivozanib at 1.5 mg oral-daily (3 weeks on, 1 week 
off) for a total of 16 weeks. At the end of the 16-week interval, those patients with 
> 25% tumor shrinkage proceeded on open label tivozanib therapy, whereas those 
patients with > 25% tumor growth (or progression as otherwise defined by 
RECIST) discontinued protocol treatment. Those patients falling between these 
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cutoffs were randomized in a 1:1 double-blind fashion to receive either tivozanib 
or placebo for the next 12 weeks, and all patients were unblinded at that point. 
Those patients without evidence of progression or intolerable adverse events with 
tivozanib were allowed to proceed on tivozanib therapy. The primary objective of 
the study was to determine the safety and efficacy of tivozanib, the latter defined 
by the objective response rate (ORR) after the first 16 weeks of open label 
therapy. A secondary objective was a comparison of PFS in subgroups within the 
randomized discontinuation phase. Ultimately, a total of 272 patients with mRCC 
were enrolled. The majority of patients had clear cell histology (83%), had 
received prior nephrectomy (73%) and were classified as intermediate risk by 
Memorial Sloan-Kettering Cancer Center (MSKCC) risk criteria (60%). After the 
16-week open-label phase, 18 and 66% of patients achieved objective response 
and stable disease respectively. The median PFS among all treated patients was 
11.7 months, with censoring performed at the time of allocation to placebo. This 
value was considerably higher (14.7 months) in the subset of patients who had 
undergone prior nephrectomy and had clear cell histology -- this observation 
accounts for the refined eligibility noted in the subsequently described Phase III 
effort. Within the randomized discontinuation phase, PFS was significantly higher 
among those patients who received tivozanib (10.3 months vs 3.3 months, p = 
0.01). The most common non-hematologic adverse events noted with tivozanib 
were hypertension, dysphonia, diarrhea and asthenia. Grade 3/4 events occurred at 
a frequency of less than 10%, with the exception of hypertension (12%) and GGT 
elevation (17%) [10]. 
The Phase III TIVO-1 trial was initiated on the basis of the compelling data for 
tivozanib monotherapy in the aforementioned randomized, Phase II study in 
mRCC. Eligibility for the study included clear cell histology with measurable 
disease and ECOG performance status between 0 - 1. Furthermore, participants 
were required to have had prior nephrectomy. Although participants may have 
had 1 prior therapy, prior use of VEGF or mTOR directed agents were not 
permitted. Patients were stratified by geographic region, the number of prior 
therapies, and the number of metastatic lesions. In a 1:1 fashion, patients were 
randomized to receive either tivozanib at 1.5 mg/day orally, 3 weeks on, 1 week 
off, or sorafenib at 400 mg oral twice daily. The primary objective of the study 
was to determine superiority of tivozanib as compared to sorafenib in terms of 
PFS, with secondary objectives including assessment of response rate, safety, and 
survival. Ultimately, a total of 517 patients were enrolled between February and 
August of 2010 at a total of 76 sites with the majority (approximately 90%) 
derived from European sites. Patient characteristics were similar on both study 
arms with an identical median age (59 years for both) and proportion of patients 
with no prior therapy (70% for both). Notably, there were a higher proportion of 
patients receiving sorafenib with an ECOG performance status of 0 (54%, as 
compared to 45% for tivozanib; p < 0.05). By independent review, there was a 
statistically significant improvement in PFS with tivozanib therapy (11.9 months 
vs. 9.1 months; p = 0.042), and this difference was slightly higher in those 
patients who had received no prior therapy (12.7 vs. 9.1 months, p = 0.037). A 
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more pronounced difference in PFS was noted by investigator assessment (14.7 
months vs. 9.6 months, p = 0.003). Subset analyses based on demographic or 
clinicopathologic characteristics showed benefit across subgroups, including 
distribution by MSKCC risk stratification. With respect to secondary endpoints, 
there was a higher proportion of objective responses with tivozanib as compared 
to sorafenib (33 vs. 23%, p = 0.014) [11].  
 Safety 
Detailed final safety data are available for 5 completed studies of tivozanib as 
monotherapy in subjects with cancer.  Treatment-emergent adverse events 
(TEAE) were defined as any adverse event (AE) not present prior to the initiation 
of study drug treatment or any AE already present that worsened in either grade or 
frequency following exposure to study drug.  With the exception of Study 
KRN951/030B01, the severity of an AE was classified based on the CTC Grading 
Scale, Version 3. For Study KRN951/03-B01, the severity of an AE was 
classified based on the NCI CTCAE Grading Scale, Version 2.0 (Grades 1 
through 4).  Safety data will be presented in relation to each study. 
Study KRN951/03-B01 was a first-in-human Phase I study in patients with 
advanced solid tumors, 3 doses of tivozanib hydrochloride were studied (1.0, 1.5, 
and 2.0 mg) in a regimen of 4 weeks of daily dosing followed by a 2-week rest 
period. Each 6-week regimen was considered one cycle. All 41 subjects enrolled 
in Study KRN951/03-B01 experienced at least 1 AE. The most frequently 
reported AEs were fatigue (27 subjects, 65.9%), hypertension (24 subjects, 
58.5%), diarrhea (23 subjects, 56.1%), hoarseness (20 subjects, 48.8%), and 
nausea (18 subjects, 43.9%). The proportion of subjects who were reported to 
have each of these AEs was higher in the 2.0 mg tivozanib hydrochloride group 
than the 1.0 and 1.5 mg tivozanib hydrochloride groups. There were 31 of 41 
subjects with at least one Grade 3/4 AE. The most frequently reported Grade 3/4 
AEs were hypertension (20 subjects, 48.8%) and fatigue (4 subjects, 9.8%). No 
other Grade 3/4 AE occurred in more than 2 subjects. Two deaths within 30 days 
of the final dose of tivozanib hydrochloride were reported in subjects participating 
in Study KRN951/03-B01. One subject in the 2 mg tivozanib hydrochloride group 
had an AE of malignant neoplasm progression during Cycle 1, which led to death. 
This AE was not considered related to study drug. One subject in the 1.0 mg 
tivozanib hydrochloride group died from disease-related causes after 3 cycles of 
treatment, 25 days after withdrawal from the study due to an AE (general physical 
health deterioration) [6]. 
Study AV-951-07-201 was a phase II randomized trial in 272 patients with 
recurrent or metastatic RCC, or primary RCC not amenable to surgery treated 
with 1.5 mg/day. TEAEs were reported in 242 of the 272 treated subjects 
(89.0%). The most frequently reported AEs were combined hypertension (125 
subjects, 46.0%), dysphonia (62 subjects, 22.8%), asthenia (61 subjects, 22.4%), 
dyspnea (51 subjects, 18.8%), and fatigue (46 subjects, 16.9%).  There were 132 
treated subjects (48.6%) who had at least 1 >= grade 3 AE. The most frequently 
reported >=Grade 3 AEs were combined hypertension (32 subjects, 11.8%), 
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asthenia (23 subjects, 8.5%), dyspnea (16 subjects, (5.9%), and GGT increased 
(15 subjects, 5.5%).  There were 15 deaths reported within 30 days of the final 
dose of tivozanib. None was considered to be related to study drug (as determined 
by the investigator) and 7 were due to disease progression [6]. 
Study AV-951-08-105 was a phase 1b multicenter study to evaluate the safety and 
activity of tivozanib in 17 subjects with NSCLC treated with either 1.0 mg or 1.5 
mg daily.  All 17 subjects in Study AV-95-08-105 experienced at least 1 AE 
during their participation in the study. The most frequently reported AEs were 
fatigue (13 subjects, 76.5%), nausea (9 subjects, 52.9%), diarrhea (8 subjects, 
47.1%), hypertension (7 subjects, 41.2%), constipation (6 subjects, 35.3%), 
stomatitis (5 subjects, 29.4%), headache (5 subjects, 29.4%), cough (5 subjects, 
29.4%), and decreased appetite (5 subjects, 29.4%). Twelve of the 17 subjects 
(70.6%) experienced at least 1 >= Grade 3 AEs occurring in more than 1 subject 
was hypertension (5 subjects, 29.4%), fatigue (3 subjects, 17.6%), and vomiting 
(2 subjects, 11.8%). Four deaths were reported in subjects participating in Study 
AV-951-08-105 (1 death due to respiratory failure and 3 deaths related to 
progressive disease/lung cancer). None of the deaths were thought to be related to 
the study drug [6]. 
Forty-five of the 50 subjects (90.0%) dosed in Study AV-951-10-112 experienced 
at least 1 AE. This was an investigational study of electrocardiogram and 
pharmacokinetic-electrocardiogram dynamics in subjects with advanced solid 
tumors treated with 1.5 mg daily of tivozanib. The most frequently reported AEs 
were hypertension (21 subjects, 42.0%), fatigue (12 subjects, 24.0%), and 
headache (11 subjects, 22.0%). Nineteen of the 50 dosed subjects (38.0%) had 
experienced at least 1 >= grade 3 TEAE. The only events reported in more than 1 
subject were hypertension (9 subjects, 18.0%) and dyspnea (2 subjects, 4.0%).  
Two of the 50 dosed subjects died both due to progression of disease (and both 
deaths were considered unrelated to study drug) [6]. 
Study AV-951-09-301 is the recently published phase III randomized trial of 1.5 
mg daily of tivozanib versus 400 mg twice daily of sorafenib in patients with 
metastatic renal cell carcinoma. Fewer patients receiving tivozanib (as compared 
to sorafenib) required dose interruptions (18% vs. 35; p < 0.001) or dose 
reductions (12 vs. 43%, p < 0.001) due to adverse events. The extent of drug 
discontinuation on account of treatment-related adverse events was similar on 
both arms (4% with tivozanib vs. 5% with sorafenib). Hypertension, diarrhea, and 
dysphonia were the most common adverse events noted with tivozanib. In 
comparing grade 3/4 toxicities, hypertension was more frequent with tivozanib 
(26 vs. 17%), whereas hand-foot syndrome was more common with sorafenib (17 
vs. 2%). The development of hypertension was noted to be a clinical biomarker 
predictive of efficacy, a phenomenon observed among other VEGF-TKIs for 
mRCC. Those patients with a diastolic blood pressure greater than 90 mmHg had 
an improved PFS with tivozanib (18.3 months vs. 9.1 months). Similarly, a 
systolic pressure greater than 150 mmHg developed while on study conferred a 
benefit in the same endpoint (16.7 months vs. 9.0 months) [11]. 
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 Clinical Pharmacology 
Final PK data are available for 3 monotherapy studies (KRN951/03-B01, AV-
951-07-201, and AV-951-08-105) and 2 combination therapy studies (AV-951-
07-102 and AV-951-08-104) in subjects with cancer. Additionally, final PK data 
are available for 2 healthy volunteer studies (Studies AV-951-09-109 and AV-
951-10-111). 
In summary, across studies, median time to peak serum concentration, (tmax), of 
tivozanib (free base), ranges from about 2 to 24 h with substantial variability 
between subjects. In studies from healthy volunteers with detailed sampling 
regimens in the first 24 h, median Tmax is 10 h. Across the multiple studies, 
exposure (Cmax and AUC) of tivozanib (free base) generally increases in a 
roughly dose proportional manner and accumulation at steady-state is 
approximately 6-7 times single dose levels. This accumulation is consistent with 
the long t1⁄2 of tivozanib (free base), the mean between studies being 
approximately 3.6 to 4.7 days. Also, the PK of tivozanib (free base) is similar in 
oncology patients compared to the profile in healthy volunteers. 
In combination studies of tivozanib hydrochloride with temsirolimus (AV-951-
07-102) and in another with paclitaxel (AV-951-08-104), there was no indication 
of a PK interaction that influenced tivozanib (free base) levels or those of the 
coadministered agent.  Data from the mass balance study (Study AV-951-10-111) 
found that 79.3% of the total radioactivity was recovered from feces. Urine 
contained no detectable tivozanib (free base) but various metabolites were 
detected in urine and accounted for 11.8% of recovered radioactivity. The 
findings are consistent with elimination of tivozanib (free base) via feces and 
some degree of metabolism. 
In vitro data suggest the possibility that tivozanib hydrochloride may interact with 
CYP3A4 inducers and/or inhibitors. Formal drug-drug interaction studies are 
currently underway to assess whether such interactions may be clinically relevant. 
Data are not yet available from these studies [6]. 
 Drug-Drug Interaction Studies 
Results from drug-drug interaction studies conducted in vitro indicate that 
tivozanib hydrochloride had no inhibitory effect on CYP3A4, CYP2C8, CYP2D6, 
CYP1A2, CYP2C9, or CYP2C19. Further, tivozanib hydrochloride did not show 
any propensity to induce CYP450 isoforms in an in vitro assay system at 
clinically relevant exposures. Due to the low likelihood of tivozanib 
hydrochloride causing a drug-drug interaction by inhibiting the metabolism of a 
co-administered agent, no clinical studies to evaluate this question are planned. 
In vitro studies with cDNA-derived CYP450 showed that only CYP1A1 
(primarily extrahepatic) and CYP3A4 were capable of metabolizing tivozanib 
hydrochloride.  Clinical trials in healthy volunteers investigating the effect of 
ketoconazole (AV-951-11-116) and rifampin (AV-951-11-117) are in progress 
[6]. 
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1.3 
Study Rationale 
 Angiogenesis and Tumor Growth 
Angiogenesis is defined as the formation of new blood vessels from preexisting 
vasculature. Angiogenesis is classified into 2 types: physiologic and pathologic. 
Physiologic angiogenesis includes embryonic development, reproduction, and 
wound healing. Pathologic angiogenesis is involved in diseases such as cancer, 
rheumatoid arthritis, and diabetic retinopathy. Angiogenesis plays an important 
role in the control of cancer progression and metastasis. Tumors cannot grow 
beyond 2 to 3 mm3 in size in the absence of the new vascularization. While 
angiogenesis is a complex process involving endothelial cell proliferation, 
survival migration, vessel morphogenesis and maturation, signaling through 
endothelial growth factors such as the VEGF ligands is known to be rate limiting 
for angiogenesis. Inhibiting tumor angiogenesis is believed to be a promising 
therapeutic modality [12]. 
 
 
 Vascular Endothelial Growth Factor Pathway 
The vascular endothelial growth factor (VEGF) signaling pathway appears 
to be the dominant pathway involved in tumor angiogenesis. The VEGF 
family consists of five structurally related proteins (VEGF-A, VEGF-B, 
VEGF-C, VEGF-D and Placental Growth Factor (PLGF), and signaling 
through this pathway is mediated by the binding of these growth factors to 
three receptors (VEGFR-1, VEGFR-2, and VEGFR-3). The ligands bind 
each receptor with distinct but overlapping specificity as well as distinct 
biological function, together acting to effect proliferation, migration and 
morphogenesis of endothelial cells to form functional vasculature [13]. 
 
 Vascular Endothelial Growth Factor Receptor 
Two high-affinity cognate endothelial receptors for VEGF have been 
identified. One is VEGF receptor-1 (VEGFR-1, also known as Flt1) and 
the other is VEGFR-2 (also known as kinase insert domain-containing 
receptor (KDR)/Flk1). These receptors have a characteristic structure with 
7 immunoglobulin-like domains in the extracellular domain and a 
cytoplasmic tyrosine kinase domain with a long kinase insert region. They 
are members of a large family of receptor tyrosine kinases and are 
localized on endothelial cells. Activation of VEGFR-1 and VEGFR-2 
receptors occurs through ligand binding, which facilitates receptor 
dimerization and autophosphorylation of tyrosine residues. VEGFR-2 is 
considered the major mediator of the mitogenic, angiogenic and 
permeability-enhancing effects of VEGF. In addition, recent studies have 
also suggested the role of VEGFR-3 (FLT-4), another tyrosine kinase, in 
tumor angiogenesis. VEGFR-3 is expressed in the tumor vasculature and 
targeting its activity is known to retard tumor formation by inhibiting 
angiogenesis [14]. 
 
Tivozanib hydrochloride is a highly potent, selective inhibitor of the 
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receptor tyrosine kinase activity of VEGFR-1, 2, and 3. It has been shown 
to block various VEGF-induced biologic responses in endothelial cells in 
vitro. Furthermore, tivozanib hydrochloride demonstrated a marked 
antitumor activity against human tumor xenograft models in nude mice 
and nude rats. Tivozanib hydrochloride has good pharmacokinetic profiles 
in various animal models. In toxicology studies conducted using Good 
Laboratory Practices, toxicities were similar across species, were generally 
dose responsive and showed signs of recovery following cessation of 
treatment. Tivozanib hydrochloride has exhibited significant anti-tumor 
effects against a wide variety of tumors in rat and mouse xenograft 
models. Pharmacologic studies showed that tivozanib hydrochloride is a 
potent inhibitor of VEGFR phosphorylation, which plays a major role in 
tumor angiogenesis and vascular permeability, but does not have obvious 
direct tumorcidal activity. These data indicated that the mechanism of the 
anti-tumor activity for tivozanib hydrochloride is through the inhibition of 
tumor angiogenesis and vascular permeability [6]. 
 
 
 Rationale for Clinical Trial Design 
This is a single arm phase II trial. All patients will receive 1.5 mg orally of 
tivozanib given daily for 3 weeks with one week off to complete a 4 week cycle.  
At the start of each cycle, patients will have a visit with a clinician who will 
obtain a pertinent history, perform a physical exam, draw serum CA-125 values 
and a CBC and CMP and determine if the patient is appropriate for therapy.  
Treatment will continue until documented disease progression or the patient is 
unable to tolerate further therapy due to excessive toxicity. 
 
2 
STUDY OBJECTIVES 
 
2.1 
Primary 
The primary objective of this single-arm, phase II clinical trial will be to determine the 
clinical activity of tivozanib in patients with platinum-resistant, recurrent ovarian, 
fallopian tube or primary peritoneal cancer.  For this protocol text, these disease entities 
will be referred to collectively as ovarian cancer. The primary endpoint of this trial will 
be the overall response rate of patients with platinum-resistant ovarian cancer to 
treatment with single agent tivozanib as measured by physical exam findings, serum CA-
125 levels and/or measurement of index lesions via appropriate imaging studies using 
RECIST criteria. 
 
2.2 
Secondary 
 The secondary objectives of this trial will include determining the potential 
survival advantage and characterizing the safety of single agent tivozanib in 
patients with platinum-resistant ovarian cancer. 
 The secondary endpoints will include the duration of progression-free survival in 
patients with platinum-resistant ovarian cancer treated with single agent tivozanib.  
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Additionally, toxicity will be reported using Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.03. 
 
2.3 
Exploratory 
 The first exploratory endpoint is a retrospective analysis of archival tissue from 
all patients who have enrolled to measure the expression of proteins that play a 
role in VEGF signaling and other relevant oncogenic pathways.  The level of 
expression will be correlated with the best response to treatment (CR, PR, SD, 
PD). 
 The second exploratory endpoint is a retrospective analysis of genetic reports 
from all patients who have enrolled, if available. This analysis will be used to 
correlate genetic mutation burden with response to treatment. 
 
3 
PATIENT SELECTION 
The target population for this study is patients with recurrent or persistent, platinum resistant 
epithelial ovarian, fallopian tube or primary peritoneal carcinoma. This will be a multicenter trial 
conducted at Northwestern Medicine.  Northwestern University will serve as the lead site and 
coordinating center for this study. Participating sites will include Northwestern Medicine Cancer 
Center Warrenville and the Northwestern Medicine Cancer Center Delnor and Northwestern 
Lake Forest Hospital. 
 
A total of 30 subjects will be needed for this trial. Approximately 6 potentially eligible patients 
are seen per month, and it is anticipated that at least 3 per month will be accrued (once all sites 
are up and running). Potential patients may be referred to the Principal Investigator (PI) at 
Northwestern University, Dr. Daniela Matei, at (312) 472-4684, or to the local PI at each 
participating site. 
 
Eligibility will be evaluated by the study team according to the following criteria. Eligibility 
waivers are not permitted. Subjects must meet all of the inclusion and none of the exclusion 
criteria to be registered to the study. Study treatment may not begin until a subject is registered. 
Please refer to Section 10 for complete instructions regarding registration procedures. 
 
3.1 
Inclusion Criteria 
Each patient must meet all of the following inclusion criteria to be enrolled in the study: 
 
 Patients must have recurrent or persistent, platinum resistant or refractory 
epithelial ovarian, fallopian tube or primary peritoneal carcinoma.  Platinum-
resistant disease is defined as a recurrence within 6 months of completing 
platinum-based chemotherapy.   
 Patients must have measurable disease or non-measurable (detectable) disease: 
o Measurable disease is defined as at least one lesion that can be accurately 
measured in at least one dimension (longest diameter to be recorded). Each 
lesion must be greater than or equal to 10 mm when measured by CT, MRI or 
by clinical exam; or greater than or equal to 20 mm when measured by chest 
x-ray. Lymph nodes must be greater than or equal to 15 mm in short axis 
when measured by CT or MRI. 
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o Non-measurable (detectable) disease in a patient is defined in this protocol as 
one who does not have measurable disease based on RECIST criteria but does 
have a CA-125 greater than or equal to two times the upper normal limit 
within the last 60 days (confirmatory at baseline) and at least one of the 
following conditions: 
• Ascites and/or pleural effusion attributed to tumor  
• Hypermetabolic lesions on PET Scan  
 
 
 
 
 
 
 Patients with measurable disease must have at least one target lesion as defined by 
RECIST 1.1 to be used to assess response on this protocol.  
 Patients must have an ECOG Performance Status of 0, 1, or 2. 
 Patients must have had one prior taxane and platinum-based chemotherapeutic 
regimen for management of primary disease containing carboplatin, cisplatin, or 
another organoplatinum compound. This initial treatment may have included 
intraperitoneal therapy, consolidation, non-cytotoxic (biologic/targeted agents) or 
extended therapy administered after surgical or non-surgical assessment.  There is 
no maximum number of prior regimens.   
Note: Use of bevacizumab as maintenance therapy after initial adjuvant platinum-
based chemotherapy is allowed so long as platinum-resistant recurrence occurred 
subsequent to a separate platinum-based regimen AND more than 6 months after 
completion of bevacizumab maintenance. 
 Patients must have signed an approved informed consent and authorization 
permitting the release of personal health information. 
 Patients must be willing and able to complete all study procedures. 
 Patients must have adequate organ or bone marrow function within 28 days prior 
to study registration, as defined below:  
Hemoglobin 
≥ 9.0 g/dL 
Absolute neutrophil count 
(ANC) 
≥ 1500 per mm3 
 
Platelet count 
≥ 100,000 per mm3 
Total bilirubin1 
≤ 1.5 × ULN (or ≤ 2.5 x ULN for subjects 
with asymptomatic Gilbert’s syndrome) 
Aspartate aminotransferase 
(AST) or alanine 
aminotransferase (ALT)1 
≤ 2.5 × ULN (or ≤ 5 × ULN for subjects 
with liver metastasis)  
 
Alkaline phosphatase 
≤ 2.5 × ULN (or ≤ 5 × ULN for subjects 
with liver or bone metastasis) 
 
Creatinine 
≤ 2.0 × ULN;  
PT/ PTT 
PT such that INR ≤ 1.5 x ULN (unless a 
patient is on therapeutic warfarin) or a 
PTT ≤ 1.5 x ULN 
Proteinuria 
≤ 2+ by urinalysis or urine dipstick 
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1. Also excluded are patients with elevations in BOTH total bilirubin > ULN AND 
AST or ALT > ULN 
 
 Patients must be greater than or equal to 18 years of age. 
 Females of child-bearing potential (FOCBP) and males must agree to use 
adequate contraception (male or female condoms, diaphragms, and spermicides, 
which are creams or gels that contain a chemical to kill sperm) prior to study 
entry, for the duration of study participation, and for 45 days following 
completion of therapy.  
NOTE: A FOCBP is any woman (regardless of sexual orientation, having 
undergone a tubal ligation, or remaining celibate by choice) who meets the  
following criteria: 
• 
Has not undergone a hysterectomy or bilateral oophorectomy 
• 
Has had menses at any time in the preceding 12 consecutive months 
(and therefore has not been naturally postmenopausal for > 12 months) 
 
 FOCBP must have a negative pregnancy test within 7 days prior to registration on 
study.  
 Patients must have the ability to understand and the willingness to sign a written 
informed consent prior to registration on study. 
3.2 
Exclusion Criteria 
Patients meeting any of the following exclusion criteria are not to be enrolled in the 
study: 
 Patients who have had previous treatment with tivozanib are excluded. 
 Patients with symptomatic left ventricular dysfunction or baseline left ventricular 
ejection fraction (LVEF) my multigated acquisition scan (MUGA) or 
echocardiogram (ECHO) of ≤ 50% are not eligible. 
 
 Patients with uncontrolled hypertension as defined as systolic blood pressure of 
>140mmHg or diastolic blood pressure of >90mmHg documented on 2 
consecutive measurements taken at least 24 hours apart are not eligible. 
Note: Initiation or adjustment of antihypertensive medication(s) is permitted prior 
to study entry. Following antihypertensive medication initiation or adjustment, 
blood pressure (BP) must be re-assessed three times at approximately 2-minute 
intervals. At least 24 hours must have elapsed between anti-hypertensive 
medication initiation or adjustment and BP measurement. These three values will 
be averaged to obtain the mean diastolic blood pressure and the mean systolic 
blood pressure. The mean SBP / DBP ratio must be < 140/90 mmHg in order for 
a subject to be eligible for the study (see Table 6.1 for details on BP control and 
reassessment). 
 
 Patients with significant cardiovascular disease are excluded, including: 
• Myocardial infarction, severe angina, or unstable angina within 6 
months prior to administration of first dose of study drug. 
• History of serious ventricular arrhythmia (i.e., ventricular tachycardia 
or ventricular fibrillation). 
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• Cardiac arrhythmias requiring anti-arrhythmic medications (except for 
atrial fibrillation that is well controlled with anti-arrhythmic 
medication). 
• Coronary or peripheral artery bypass graft within 6 months of 
screening. 
• History of Class III or IV congestive heart failure, as defined by the 
New York Heart Association. 
 
 Patients with central nervous system metastases are excluded. 
Note: Subjects with previously treated (radiotherapy or surgery) brain 
metastasis that have been stable without steroid treatment for at least 3 
months following prior treatment may be enrolled. 
 
 Any patient with a current non-healing wound, bone fracture, or skin ulcer is 
excluded. 
 Patients who are currently receiving treatment with drugs known to be strong 
inhibitors or inducers of isoenzyme CYP3A4 including herbal medications (See 
Appendix B for further information). 
Note: As this list is constantly evolving, if a medication is incorrectly 
documented as prohibited in this protocol, documentation from the site 
pharmacist to the contrary will be acceptable for the purposes of 
registration. 
 
 Active peptic ulcer disease, inflammatory bowel disease, ulcerative colitis, or 
other gastrointestinal condition with increased risk of perforation; history of 
abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 
4 weeks prior to administration of first dose of study drug. 
 Serious/active infection or infection requiring parenteral antibiotics.  
 Patients must not have a corrected QT interval (QTc) of > 480 msec using 
Bazett’s formula. 
 Patients who have had radiotherapy or minor surgical procedure within 14 days, 
or major surgical procedure within 28 days prior to administration of first dose of 
study drug are not eligible; patients with inadequate recovery from prior surgical 
procedure are also not eligible. 
 Patients with active infection requiring antibiotics are not eligible (with the 
exception of uncomplicated UTI and uncomplicated respiratory tract infections). 
 Patients may not have had any prior systemic therapy ≤ 21 days prior to 
registration for treatment of ovarian cancer. 
 
 Patients who have received investigational or licensed drugs that target vascular 
endothelial growth factor [VEGF] or VEGF receptors/pathways (such as 
bevacizumab, sorafenib, pazopanib, sunitinib, axitinib, cabozantinib, etc.) for the 
treatment of recurrent cancer are not eligible. Exceptions: prior treatment with 
bevacizumab in the up-front or maintenance setting is allowed, provided the 
patient had a favorable response to bevacizumab. Favorable response is defined as 
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having had a disease free interval of >6 months following completion of a 
bevacizumab-containing regimen. If questions, contact the PI. 
 Significant thromboembolic or vascular disorders within 6 months prior to 
administration of first dose of study drug, including but not limited to:   
• 
Deep vein thrombosis 
• 
Pulmonary embolism 
• 
Cerebrovascular accident (CVA) or transient ischemic attack (TIA) 
• 
Peripheral arterial ischemia > Grade 2 (per National Cancer Institute [NCI] 
Common Terminology Criteria for Adverse Events [CTCAE] Version 4.03)  
 
 Significant bleeding disorders within 6 months prior to administration of first 
dose of study drug, including but not limited to: 
• 
Hematemesis, hematochezia, melena or other gastrointestinal bleeding ≥ 
Grade 2 (per CTCAE Version 4.03) 
• 
Hemoptysis or other pulmonary bleeding ≥ Grade 2 (per CTCAE Version 
4.03) 
• 
Hematuria or other genitourinary bleeding ≥ Grade 2 (per CTCAE Version 
4.03) 
 
 Currently active second primary malignancy, including hematologic malignancies 
(leukemia, lymphoma, multiple myeloma, etc.), other than non-melanoma skin 
cancers, in situ cervical cancer, and ductal or lobular carcinoma in situ of the 
breast.  Subjects are considered to have a currently active malignancy if they have 
completed anti-cancer therapy and have not been disease free for > 2 years. 
 Pregnant or lactating females are excluded. 
 Any patient with a history of genetic or acquired immune suppression disease 
such as human immunodeficiency virus (HIV) is excluded; subjects on immune 
suppressive therapy for organ transplant are also excluded.  
 Life-threatening illness or organ system dysfunction compromising safety 
evaluation. 
 Requirement for hemodialysis or peritoneal dialysis. 
 Inability to swallow capsules, malabsorption syndrome or gastrointestinal disease 
that severely affects the absorption of study drugs, major resection of the stomach 
or small bowel, or gastric bypass procedure.  
 Known hypersensitivity to drugs chemically related to tivozanib hydrochloride or 
sunitinib or their excipients. 
 Psychiatric disorder or altered mental status precluding informed consent or 
protocol-related testing. 
 Patients with clinical symptoms or signs of gastrointestinal obstruction. 
 
4 
TREATMENT PLAN 
 
4.1 
Overview 
This is a single arm phase II trial. All patients will receive 1.5 mg orally of tivozanib 
given daily for 3 weeks with one week off to complete a 4 week cycle.  At the start of 
each cycle, patients will have a visit with a clinician who will obtain a pertinent history, 
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perform a physical exam, draw serum CA-125 values and a CBC and CMP and 
determine if the patient is appropriate for therapy.  Treatment will continue until 
documented disease progression or the patient is unable to tolerate further therapy due to 
excessive toxicity. 
 
4.2 
Study Drug Administration: Tivozanib 
 Drug Dispensing: The patient will be dispensed enough pills for 1 cycle at each 
monthly visit. Patient pill calendar will be reviewed by study coordinator or nurse. 
Pill count will be done, and any unused pills will be returned each cycle.    
 Dosing Schedule:  Tivozanib hydrochloride will be administered orally, at a dose 
of 1.5 mg/day, beginning on Day 1 of Cycle 1. Subjects will receive tivozanib 
hydrochloride once daily for 3 weeks followed by 1 week off treatment. One 
cycle is defined as 4 weeks. Cycles will be repeated every 4 weeks in the absence 
of disease progression or unacceptable toxicities. 
 
 Dosing Information:  The prescribed daily dose of tivozanib hydrochloride is to 
be taken, once per day, preferably in the morning, with water. Tivozanib should 
be taken on an empty stomach either 1 hour before or 2 hours after meals at the 
same time each day. The tablets should be swallowed whole and cannot be 
crushed or broken. Only one capsule of tivozanib hydrochloride should be taken 
each day. 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 delayed. 
 Dosing Parameters: Subsequent cycles of therapy will not begin (day 1 of each 
cycle) until the ANC is ≥1500 cells/mcl and the platelet count is ≥ 100,000/mcl. 
Therapy will be delayed for a maximum of two weeks until these values are 
achieved. Patients who fail to recover adequate counts within a two week delay 
will be removed from study therapy.  Grade 1 or 2 toxicity will not result in a 
dose reduction or treatment delay.  Drug-related grade 3 or 4 toxicities will result 
in an interruption in treatment until the toxicity is less than or equal to grade 2.  
Additionally, a dose reduction will be performed. If there is no recovery to ≤ 
grade 2 or recurrent grade 3 or 4, then tivozanib will be discontinued. 
 
4.3 
General Concomitant Medication and Supportive Care Guidelines 
 Premedications for Study Drug-Related Toxicities 
 Patients should not be premedicated prior to receiving the first dose of study 
drug. 
 Thereafter, patients having experienced symptoms suggesting mild to 
moderate study drug administration-related reactions may be premedicated 
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with standard measures (eg, acetaminophen, diphenhydramine, H2-blockers, 
and/or dexamethasone), as clinically indicated. 
 Mandatory premedication will be recommended for all patients treated on 
this study should a pattern of mild to moderate study drug administration-
related reactions begin to emerge. 
 Any medications administered for either prophylaxis or therapy of symptoms 
considered to be associated with study drug will be documented and reported. 
Subjects should avoid agents known to be weak Cytochrome P450 
(CYP3A4) inducers or inhibitors for the duration of study 
treatment.  See Appendix B for further information on Cytochrome 
P450 (CYP3A4) inducers and inhibitors. 
 
 Concomitant Medications 
The following medications/treatments are prohibited during study treatment: 
 
 Chemotherapy, biological therapy (including cytokines, signal transduction 
inhibitors, monoclonal antibodies), immunotherapy or any other systemic 
therapy for ovarian, fallopian tube or primary peritoneal cancer. 
 Treatment with radiotherapy (including palliative) 
 Strong/moderate Cytochrome P450 (CYP3A4) inducers or inhibitors for the 
duration of study treatment.  All CYP3A4 inducers and inhibitors should be 
used with caution (See Appendix B for further information). 
Note: As this list is constantly evolving, if a medication is incorrectly 
documented as prohibited in this protocol, documentation from the site 
pharmacist to the contrary will be acceptable for the purposes of 
registration. 
 Subjects will NOT receive prophylactic growth factors [filgrastim (G-CSF), 
sargramostim (GM-CSF), pegfilgrastim (Neulasta)] unless they experience 
recurrent neutropenic complications after treatment modifications specified 
below. 
 Subjects will NOT receive prophylactic thrombopoietic agents. 
 Subjects may not receive erythropoietin (EPO) but may receive iron 
supplements, and/or transfusions as clinically indicated for management of 
anemia.  
 The following medications/treatments are permitted during the study treatment: 
 Full dose oral anticoagulants and/or anticoagulation with low molecular 
weight heparin or unfractionated heparin administered subcutaneously.  
Subjects taking anticoagulants should have their coagulation panels 
monitored as scheduled during the study and as clinically indicated. 
 Subjects are permitted to receive supportive care throughout the study 
including transfusions (blood, blood products), antibiotics, anti-emetics, anti-
diarrheal agents, analgesics, or bisphosphonates, when appropriate, with the 
exception of any prohibited medications/treatments. 
 Other medications/treatments that should be avoided during the study treatment: 
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 Herbal remedies should be avoided; however, if herbal remedies are used, 
they should be documented as a concomitant medication.  
 Medications/agents known to prolong QT interval.   
 Systemic hormonal therapy, with the exception of: 
 Hormonal therapy for appetite stimulation or contraception; 
 Nasal, ophthalmic, inhaled and topical steroid preparations; 
 Hormone replacement therapy for conditions such as adrenal insufficiency, 
hypothyroidism, etc.; 
 Low dose maintenance steroid therapy (equivalent of prednisone ≤ 10 
mg/day) for other conditions. 
 
4.4 
Duration of Therapy 
Patients may continue to receive cycles of treatment until any of the following occur: 
• 
Disease progression 
• 
Development of an inter-current illness that prevents further administration of 
treatment 
• 
Unacceptable adverse event(s) 
• 
Patient decides to withdraw from either study treatment or the study as a whole  
• 
The treating investigator determines that the patient should be taken off 
treatment for any reason (i.e. changes in condition, inability to comply with 
study treatment or procedures) 
 
4.5 
Duration of Follow Up 
Patients will return for an end of treatment visit within ±14 days of the decision to 
discontinue treatment.  
 
Subjects will be followed approximately 30 days after discontinuation of 
treatment and then approximately every 3 months for 2 years and then 
approximately every 6 months for 3 years after removal from study or until death, 
whichever occurs first.  Subjects will be monitored for survival for this 5-year 
period.  Subjects removed from study for unacceptable adverse event(s) will be 
followed until resolution or stabilization of the adverse event. 
 
4.6 
Removal of Subjects from Study Treatment and/or Study as a Whole 
Patients can be taken off the study treatment and/or study as a whole at any time 
at their own request, or they may be withdrawn at the discretion of the 
investigator for safety, behavioral or administrative reasons. The reason(s) for 
discontinuation must be clearly documented on the appropriate eCRF and may 
include: 
• Patient voluntarily withdraws from treatment (follow-up permitted) 
• Patient withdraws consent (no follow-up permitted) 
• Patient is unable to comply with protocol requirements 
• Patient demonstrates disease progression  
• Patient experiences unacceptable toxicity  
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• Treating physician determines that continuation on the study would not be in 
the patient’s best interest 
• Patient becomes pregnant  
• Patient develops a second malignancy that requires treatment which would 
interfere with this study 
• Patient becomes lost to follow-up (LTF)  
 
4.7 
Dose Delays/Dose Modification 
Comprehensive assessments of any toxicity experienced by the patient will be performed 
throughout the course of this study. Anticipated toxicities that may be experienced are 
detailed in the section on adverse events in prior studies of tivozanib.  Grades of toxicity 
(NCI Common Terminology for Adverse Events [CTCAE- Version 4.03]), as well as 
clinical judgment, will be used to determine appropriate management of the patient 
experiencing any adverse event while participating in this study.  Any adverse event, 
whether observed by the investigator, or observed or experienced by the patient, will be 
reported. All clinical and laboratory adverse events must be carefully evaluated for 
severity, duration and relationship to tivozanib. 
 
 Tivozanib Hydrochloride Dose Modification 
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 (excluding 
hypertension) are summarized in the table below. 
 
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 32 
Interrupt dosing3 until toxicity 
resolves to < grade 1. 
Dosing may resume at same dose or 
reduced dose at the discretion of the 
Investigator (see below for dose 
reduction guidelines). 
Grade 4 
Interrupt dosing until toxicity 
resolves to < grade 1. 
Dosing may resume at same dose or 
reduced dose at the discretion of the 
investigator (see below for dose 
reduction guidelines). 
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1. Hypertension must be treated as described in Appendix C prior to any dose modification  
2. Referring to toxicity that persists despite appropriate medical care. 
3. Tivozanib may be interrupted for up to 2 weeks. If a subject is able to resume treatment after an 
interruption of ≤ 2 weeks, missed doses will not be made up (i.e. the cycle duration will remain 
unchanged). If any drug related toxicity results in interruption of >2 weeks, the subject should be 
discontinued from study treatment unless there is clear benefit. 
 
Patients should be followed for assessment of the toxicities until the AEs resolve 
or are deemed irreversible. The maximum delay of drug administration by the 
treating investigator or the patients’ own decision for any reason, including 
toxicities, is 2 weeks. If the drug is withheld for more than 2 continuous weeks 
due to a treatment-related toxicity that does not resolve, the patient will be 
withdrawn from study treatment.  The exception is HTN, which must first be 
treated as described in Appendix C prior to any dose modification.   
Patients will be withdrawn from the study if they fail to recover to grade ≤ 1 or 
tolerable grade 2 (or within 1 grade of starting values for pre-existing laboratory 
abnormalities) from a treatment-related toxicity within 2 weeks OR if they 
experience agent related adverse events requiring dose modification despite  
previous dose reductions (i.e. would require a 2nd dose reduction) unless the 
investigator agrees that the subject should remain in the study because of evidence 
that the patient is/may continue deriving benefit from continuing study treatment. 
The appropriate reduced dose will be determined after discussion with the 
principal investigator and approval of the Data Monitoring Committee. Patients 
requiring dose reductions should not have the dose re-escalated with subsequent 
treatments.  If treatment was interrupted for < 1 week, the patient will resume 
dosing on the current treatment cycle.  If treatment was interrupted for ≥ 1 week, 
the patient will start a new cycle of treatment. 
 Tivozanib Hydrochloride Dose Reduction 
Dose reductions of tivozanib hydrochloride to 1.0 mg/day will be allowed for 
subjects with ≥ Grade 3 drug-related adverse events.  The exception is 
hypertension, which must be treated with anti-hypertensive drugs prior to dose 
reduction.  Once a subject’s dose of tivozanib hydrochloride is reduced, it may 
not be re-escalated through the remainder of the subject’s participation in the 
study.  If a subject is unable to tolerate a reduced dose due to toxicities thought to 
be related to treatment, treatment should be discontinued. 
5 
RESPONSE ASSESSMENT 
 
The measures used to determine the objective overall response rate will be those that are already 
in place for determining treatment efficacy.  Specifically, we will utilize physical exam findings 
performed at the commencement of each 4-week cycle of treatment during a clinician visit.  
Additionally, serum CA-125 levels will be checked at the commencement of each 4 week cycle 
of treatment to determine disease status.  If otherwise indicated by disease state, we will obtain 
CT scan or MRI or chest x-ray and utilize index target lesions and RECIST 1.1 criteria to 
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determine treatment efficacy and response rate. 
 
5.1 
Antitumor Effect – Solid Tumors 
Response and progression will be evaluated in this study using the international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) 
guideline (version 1.1) [16]. Changes in the largest diameter (unidimensional 
measurement) of the tumor lesions and the shortest diameter in the case of malignant 
lymph nodes are used in the RECIST criteria. 
 
5.2 
Disease Parameters 
 Measurable disease 
Measurable lesions are defined as those that can be accurately measured in at least 
one dimension (longest diameter to be recorded) as >10 mm with CT scan, as >20 
mm by chest x-ray, or >10 mm with calipers by clinical exam. All tumor 
measurements must be recorded in millimeters (or decimal fractions of 
centimeters). Lymph nodes are considered measurable in RECIST 1.1 if their 
short diameter exceeds 15 mm. Lymph nodes are considered normal if they have a 
short axis of less than 10 mm; this applies to determination of response as well. 
Lesions that are previously irradiated must show clear evidence of progression 
over a minimum of 3 months to include as measurable. This period of time is used 
to discount tumor edema in an irradiated field as a false sign of disease 
progression. 
 Non-measurable disease 
All other lesions (or sites of disease), including small lesions (longest diameter 
<10 mm or pathological lymph nodes with >10 to <15 mm short axis), are 
considered non-measurable disease. Bone lesions, leptomeningeal disease, ascites, 
pleural/pericardial effusions, lymphangitis cutis/pulmonis, inflammatory breast 
disease, abdominal masses (specifically abdominal masses that cannot be 
followed by CT or MRI), and cystic lesions are all non-measurable. 
Note: Bone lesions: Lytic bone lesions or mixed lytic-blastic lesions, with 
identifiable soft tissue components, that can be evaluated by CT or MRI 
can be considered as measurable lesions if the soft tissue component 
meets the definition of measurability described above. Blastic bone lesions 
are non-measurable. 
 
Cystic lesions that meet the criteria for radiographically defined simple 
cysts should not be considered as malignant lesions (neither measurable 
nor non- measurable) since they are, by definition, simple cysts. ‘Cystic 
lesions’ thought to represent cystic metastases can be considered as 
measurable lesions, if they meet the definition of measurability described 
above. However, if non-cystic lesions are present in the same patient, 
these are preferred for selection as target lesions. 
 
 Target lesions 
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All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in 
total, representative of all involved organs, should be identified as target lesions 
and recorded and measured at baseline. Target lesions should be selected on the 
basis of their size (lesions with the longest diameter) and their suitability for 
accurate repeated measurements (either by imaging techniques or clinically). A 
sum of the longest diameter (LD) for all target lesions will be calculated and 
reported as the baseline sum LD. The baseline sum LD will be used as reference 
by which to characterize the objective tumor response. 
 Non-target lesions 
All other lesions (or sites of disease) including any measurable lesions over and 
above the 5 target lesions should be identified as non-target lesions and should 
also be recorded at baseline. Measurements of these lesions are not required, but 
the presence, absence, or in rare cases unequivocal progression of each should be 
noted throughout follow-up. 
 
5.3 
Methods 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 28 days 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 when both methods have 
been used to assess the antitumor effect of a treatment. 
 
 Clinical lesions 
Clinical lesions will only be considered measurable when they are >= 10 mm 
diameter. For superficial lesions measured by caliper, documentation by color 
photography including a ruler in the field of view is strongly 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), but NOT lung. 
Use of MRI remains a complex issue. MRI has excellent contrast, spatial, and 
temporal resolution; however, there are many image acquisition variables 
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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, subsequent image acquisitions should use the same type of 
scanner and follow the baseline imaging protocol as closely as possible. If 
possible, body scans should be performed with breath-hold scanning techniques. 
 
 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. PET-CT scans are not always done with oral and IV contrast. In 
addition, the PET portion of the CT introduces additional data that may bias an 
investigator if it is not routinely or serially performed. For these reasons, we will 
not allow PET-CT use for RECIST 1.1 response criteria. 
 
 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. 
Note: A “positive” FDG-PET scan lesion means one that is FDG 
avid with an uptake greater than twice that of the surrounding 
tissue on the attenuation corrected image. 
 
 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 
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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. 
 CA-125 (Ovarian, fallopian tube and primary peritoneal cancer trials)  
If CA125 is initially above the upper normal limit then it may be used as a marker 
of treatment efficacy. It must normalize for a patient to be considered in complete 
clinical response. Specific guidelines for CA-125 response (in recurrent ovarian 
cancer) have been published [15]. In addition, the Gynecologic Cancer Intergroup 
has developed CA-125 progression criteria that are to be integrated with objective 
tumor assessment for use only in first-line trials in ovarian cancer [17].   See 
section 5.4.3 for explanation of 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. 
It is mandatory to obtain cytological confirmation of the neoplastic origin of any 
effusion that appears or worsens during treatment when measurable disease has 
met criteria for response or stable disease. This confirmation is necessary to 
differentiate response or stable disease versus progressive disease, as an effusion 
may be a side effect of the treatment. 
5.4 
Response Criteria 
Determination of response should take into consideration all target and non-target lesions 
and, if appropriate, biomarkers. 
 
 
 Evaluation of Target Lesions 
Complete Response (CR): Disappearance of all target lesions. Any pathological 
lymph nodes (whether target or non-target) must have reduction in short axis to 
<10 mm. 
Partial Response (PR): At least a 30% decrease in the sum of the diameters of 
target lesions, taking as reference the baseline sum diameters. 
Progressive Disease (PD): At least a 20% increase in the sum of the diameters of 
target lesions, taking as reference the smallest sum on study (this includes the 
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baseline sum if that is the smallest on study). In addition to the relative increase of 
20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: 
the appearance of one or more new lesions is also considered progressions). 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum diameters while 
on study. 
 Evaluation of Non-Target Lesions 
Complete Response (CR): Disappearance of all non-target lesions. All lymph 
nodes must be non-pathological in size (<10 mm short axis). 
Note: If CA-125 is initially above the upper normal limit, it must normalize for a 
patient to be considered in complete clinical response. 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s)  
Progressive Disease (PD): Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions. Unequivocal progression 
should not normally trump target lesion status. It must be representative of overall 
disease status change, not a single lesion increase. 
Not evaluable (NE): When at least one non-target lesion is not evaluated at a 
particular time point. 
Although a clear progression of only ‘non-target’ lesions is exceptional, the 
opinion of the treating physician should prevail in such circumstances, and the 
progression status should be confirmed at a later time by the review panel (or 
Principal Investigator). 
 Evaluation of Biomarkers 
If serum CA-125 is initially above the upper normal limit, it must normalize for a 
patient to be considered in complete clinical response.  A partial response 
according to CA 125 has occurred if there is at least a 50% reduction in CA 125 
levels from a pretreatment sample but the value remains above the normal range. 
The response must be confirmed and maintained for at least 28 days.  A complete 
response has occurred if the CA-125 level decreases into the normal range.  
Progressive disease will be defined as a doubling of CA-125 levels.  Stable 
disease will be any CA-125 level that falls within the range of progressive disease 
and partial response. 
5.5 
Duration of Response 
 Duration of overall response 
The duration of overall response is measured from the time measurement criteria 
are met for CR or PR (whichever is first recorded) until the first date that 
recurrent or progressive disease is objectively documented (taking as reference for 
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progressive disease the smallest measurements recorded since the treatment 
started). 
The duration of overall CR is measured from the time measurement criteria are 
first met for CR until the first date that progressive disease is objectively 
documented. 
 Duration of stable disease 
Stable disease is measured from the start of the treatment until the criteria for 
progression are met, taking as reference the smallest measurements recorded since 
date of study entry, including the baseline measurements. 
5.6 
Progression-Free Survival 
Progression-Free Survival (PFS) is defined as the duration of time from study entry to 
time of progression or death, whichever occurs first. 
 
5.7 
Survival 
Survival is defined as the duration of time from study entry to time of death or the date of 
last contact. 
 
6 
DRUG INFORMATION 
 
6.1 
Tivozanib Hydrochloride 
 Other Names 
AV-951 
 Classification 
VEGFR tyrosine kinase inhibitor 
 Molecular Formula and Weight  
C22H19ClN4O5 HCl H2O 509.34 (hydrochloride monohydrate) 454.86 (free base) 
 Chemical Name 
 N-{2-Chloro-4-[(6,7-dimethoxy-4-quinolinyl)oxy]phenyl}-N'-(5-methyl-3- 
isoxazolyl) urea hydrochloride monohydrate 
 Mechanism of Action: 
Tivozanib is a highly potent inhibitor of vascular endothelial growth factor 
(VEGF) receptor tyrosine kinases (VEGFR1, VEGFR2, and VEGFR3). Vascular 
endothelial growth factor receptor inhibition may block VEGF driven 
angiogenesis and, as a consequence, constrain tumor growth. 
 Drug Storage and Stability 
Tivozanib hydrochloride drug product should be stored at room temperature (15o– 
25oC) in a controlled access room that can be entered only by authorized 
pharmacy or investigative personnel. 
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Long-term stability studies conducted according to ICH guidelines support an 
expiration dating of 36 months for dose strengths ranging from 0.5 mg to 2.0 mg 
when stored at 15-25ºC with allowable excursions up to 30ºC.  Tivozanib 
hydrochloride drug product is an investigational new drug. Accordingly, all drug 
handling and disposal procedures for orally administered investigational drugs 
should be performed by qualified personnel as documented by the American 
Hospital Formulary Service or other recognized formulary requirements. 
 Protocol Dose 
The following dosage strengths will be made available: 
1.5 mg 
1.0 mg 
The amount of study drug dispensed to the subject at the beginning of each dosing 
cycle will be sufficient to allow for 3 weeks (21 days) of consecutive once-daily 
dosing of tivozanib hydrochloride. Dosing compliance will be monitored at each 
clinic visit. 
 Route of Administration  
Tivozanib hydrochloride is formulated for oral administration as a white opaque 
number 4 gelatin capsule.   
 Availability 
Provided at free of charge by AVEO Pharmaceuticals, Inc.   
 Approximate Solubility 
Practically insoluble in water, slightly soluble in methanol, very slightly soluble 
in ethanol, and freely soluble in dimethyl sulfoxide. 
Complete study drug information (including packaging, labeling, storage and 
disposition) is provided in the Tivozanib Hydrochloride Investigator’s Brochure 
(IB). 
 
IRB #: STU00073756-CR0005 Approved by NU IRB for use on or after 12/17/2019 through 12/16/2020.


Northwestern University 
 
                                                       
Study Number: NU12G11 
36 
 
Initial Version Date: 04/28/2013 
 
 
Amendment 8: 1/3/2019 
 
7 
CLINICAL AND LABORATORY EVALUATIONS 
7.1 
Schedule of Assessments 
Parameter 
Pre-
Therapy 
Weekly 
(-1 
Day) 
Prior to 
Each Cycle 
(-4 Days)  
Every Odd 
Cycle (-7 
Days) 
End of 
Treatment Visit 
(±14 Days)12 
Follow Up 
History and Physical Exam 
X2 
 
X 
 
 
 
Vital signs (Blood Pressure, Heart Rate and 
Temperature) 
X2 
X 
X 
 
 
 
ECOG Performance Status 
X2 
 
X 
 
 
 
Toxicity Assessment5 
X2 
X4 
X 
 
X 
 
CBC/Differential/Platelets 
X2 
X3 
X6 
 
 
 
PT/INR and PTT 
X2,7 
 
 
 
 
 
CMP + electrolytes14 
X2 
X3 
X6 
 
 
 
Total bilirubin, AST, ALT, Alkaline Phosphatase 
X2 
X3 
X6 
 
 
 
Urine Pregnancy Test (if childbearing potential 
exists) 
X2 
 
 
 
 
 
X-ray or CT or MR imaging 
(chest/abdomen/pelvis) 
X1 
 
 
X11 
X11 
 
Radiographic tumor measurement 
X1 
 
 
X11 
X11 
 
CA-125 
X1 
 
X15 
 
 
 
Electrocardiogram (ECG) 
X1 
 
X15 
 
 
 
Echocardiogram (ECHO) / MUGA 
X1 
 
 
 
 
 
Urinalysis to evaluate for proteinuria 
X8 
 
 
X9, 10 
 
 
Patient Tablet Calendar 
 
 
X 
 
 
 
Follow-up Phone Call 
 
X4 
 
 
 
 
Review Con Meds16 
X2 
 
X 
 
X 
X16 
Survival Status 
 
 
 
 
 
X13 
One cycle = 28 days 
1. Must be obtained within 28 days prior to study registration. 
2. Must be obtained within 7 days prior to study registration. 
3. During the first two cycles of therapy patients should have CBC and CMP performed weekly while taking study medication. 
Magnesium and Phosphorus are only required weekly during the first two cycles if clinically indicated. Thereafter the patient can be 
seen prior to each cycle. 
4. Weekly toxicity assessment performed during for cycle 1 only.  Assessment can be done at a clinic visit, by phone or by email. 
5. Report all adverse events that occur within 30 days of last protocol treatment of therapy administered.  


Northwestern University 
 
                                                       
Study Number: NU12G11 
37 
 
Initial Version Date: 04/28/2013 
 
 
Amendment 8: 1/3/2019 
 
6. Must be obtained within 4 days of treatment with protocol therapy. 
7. Patients on prophylactic or therapeutic anticoagulation with warfarin should have PT/INR monitored after starting and stopping 
tivozanib (e.g., weekly for the first cycle and weekly for a minimum of 2 weeks following discontinuation of tivozanib) and weekly 
for the first cycle of treatment following a warfarin or tivozanib dose modification. 
8. Urinalysis to evaluate for proteinuria must be obtained 14 days prior to initiating protocol therapy. 
9. If protein is 3+ or higher (≥ 300 mg/dL), 24-hour urine protein should be obtained and the level must be <1000 mg (<1g/24hrs) for 
patient to continue on study.  
10. Urinalysis to evaluate for proteinuria should be performed prior to every odd cycle (for example, prior to cycles 1, 3, 5, 7, ETC).  
11. CT scan or MRI or x-ray of chest-abdomen-pelvis every other cycle (or equivalent time frame for patients off treatment prior to 
disease progression) for the first 6 months; then every 3 months thereafter until disease progression; also repeat at any other time if 
clinically indicated based on symptoms or physical signs suggestive of progressive disease; also complete at the end of treatment if 
clinically indicated. Responses (CR and PR) require confirmation at greater than or equal to 4 weeks from initial documentation (see 
section 8).  
12. End of treatment visit will occur within ±14 days of the decision to discontinue study treatment. 
13. Follow-up approximately 30 days after the last dose of Tivozanib and then approximately every 3 months for 2 years and then every 6 
months for 3 years. 
14. CMP + electrolytes includes: Sodium, potassium, chloride, bicarbonate, BUN, Glucose, Albumin, Creatinine, Calcium, Magnesium, 
Phosphorus, total protein. Magnesium and Phosphorus are only required if clinically indicated 
15. Must be completed within 14 days prior to each cycle.  Exceptions include treatment delays, in which case they would be allowed 
within 21 days prior to the delayed cycle.  
16. Record all reported concomitant medications from the time of consent until 30 days after the last dose of Tivozanib (or until initiating 
the next line of anti-cancer therapy, whichever is first).   
 


Northwestern University 
 
                        
Study Number: NU12G11 
38 
 
Initial Version Date: 04/28/2013 
 
 
Amendment 8: 1/3/2019 
 
 
8 
STATISTICAL METHODS 
 
Statistical analyses will focus on estimation of overall response rates in patients with 
platinum-resistant ovarian cancer as stated in the Primary Objective.   Specific definitions 
for complete response (CR), partial response (PR), stable disease (SD) or progressive 
disease (PD) are defined in the Primary Endpoint section according to physical exam 
findings, serum CA-125 levels and imaging studies.  Response frequencies and 
percentages will be tabulated for all four groups and then an overall frequency of 
response (CR or PR) v. non-response (SD or PD) will be calculated along with a one-
sided lower limit 95% confidence interval, consistent with the approach used to specify 
staging of accrual.  For the secondary objective, the Kaplan-Meier method will be 
utilized to estimate the median and overall distribution of progression-free survival.  
Toxicity will also be evaluated as a secondary objective and grades will be summarized 
by counts and frequencies. For description of other continuous variables, means, standard 
deviations, minimum and maximum values will be used.  Other categorical variables will 
be summarized by counts and frequencies.  In addition, the extent to which treatment is 
completed will be monitored and tabulated according to the number of complete weeks of 
treatment.    
 
Total anticipated accrual to this phase II single-arm trial is 30 patients.  Recruitment will 
be completed in two stages with 10 patients accrued in the first stage and 20 accrued in 
the second stage according to Simon’s two-stage design (Simon, 1989; Jung et al. 2004) 
with a null hypothesis that the true response rate is less than or equal to 5% and 5% type I 
error and 80% power when the true response rate is greater than or equal to 20%.  In the 
first stage, if there are 0 responses (CR or PR) in the 10 patients that are accrued, the 
study will be stopped.  Otherwise, 20 additional patients will be accrued, with rejection of 
the null hypothesis occurring if 4 or more responses are observed in the total 30 patients. 
On 10/12/16 the Northwestern DSMC reviewed the first 9 evaluable patients and 
approved the study to open to an additional 21 patients.   Calculations were conducted 
using the online software at 
http://cancer.unc.edu/biostatistics/program/ivanova/SimonsTwoStageDesign.aspx. 
 
With an expected response rate of 20%, if all 30 patients are accrued, a one-sided 95% 
lower-limit confidence interval will have a distance from the sample proportion to the 
lower limit of about 14%.  
 
For exploratory aims we will proceed as follows. The first exploratory endpoint is the 
expression of proteins that play a role in VEGF signaling and other relevant oncogenic 
pathways.  The level of expression of each protein will be correlated via ANOVA with 
response to treatment (CR, PR, SD, PD); The second exploratory endpoint is a 
retrospective genetic mutation burden to be correlated via ANOVA or contingency table 
analysis with response to treatment (CR, PR, SD, PD). 
 
 
 
IRB #: STU00073756-CR0005 Approved by NU IRB for use on or after 12/17/2019 through 12/16/2020.


Northwestern University 
 
                        
Study Number: NU12G11 
39 
 
Initial Version Date: 04/28/2013 
 
 
Amendment 8: 1/3/2019 
 
9 
ADVERSE EVENTS 
This study will be conducted in compliance with the Data Safety Monitoring Plan 
(DSMP) of the Robert H. Lurie Comprehensive Cancer Center of Northwestern 
University (please refer to Appendices for additional information). The level of risk 
attributed to this study requires high-risk monitoring as outlined in the DSMP. In 
addition, the study will abide by all safety reporting regulations, as set forth in the Code 
of Federal Regulations.   
 
9.1 
Adverse Event Monitoring 
Adverse event data collection and reporting, which are required as part of every 
clinical trial, are done to ensure the safety of subjects enrolled in the studies as 
well as those who will enroll in future studies using similar agents. Adverse 
events are reported in a routine manner at scheduled times during a trial (see 
Section 7 for timepoints). In addition, certain adverse events must be reported in 
an expedited manner to allow for optimal monitoring and patient safety and care.  
 
All patients experiencing an adverse event, regardless of its relationship to study 
drug, will be followed until:  
• the adverse event resolves or the symptoms or signs that constitute the adverse 
event return to baseline;  
• any abnormal laboratory values have returned to baseline;  
• there is a satisfactory explanation other than the study drug for the changes 
observed; or 
• death. 
 
9.2 
Definitions & Descriptions 
 Adverse Event 
An adverse event (AE) is any untoward medical occurrence in a patient receiving 
study treatment and which does not necessarily have a causal relationship with 
this treatment. An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of an experimental intervention, whether or not related to 
the intervention.  
Recording of AEs should be done in a concise manner using standard, acceptable 
medical terms. In general, AEs are not procedures or measurements, but should 
reflect the reason for the procedure or the diagnosis based on the abnormal 
measurement. Preexisting conditions that worsen in severity or frequency during 
the study should also be recorded (a preexisting condition that does not worsen is 
not an AE). Further, a procedure or surgery is not an AE; rather, the event leading 
to the procedure or surgery is considered an AE. 
If a specific medical diagnosis has been made, that diagnosis or syndrome should 
be recorded as the AE whenever possible.  However, a complete description of 
the signs, symptoms and investigations which led to the diagnosis should be 
provided. For example, if clinically significant elevations of liver function tests 
IRB #: STU00073756-CR0005 Approved by NU IRB for use on or after 12/17/2019 through 12/16/2020.


Northwestern University 
 
                        
Study Number: NU12G11 
40 
 
Initial Version Date: 04/28/2013 
 
 
Amendment 8: 1/3/2019 
 
are known to be secondary to hepatitis, “hepatitis” and not “elevated liver 
function tests” should be recorded. If the cause is not known, the abnormal test or 
finding should be recorded as an AE, using appropriate medical terminology (e/g/ 
thrombocytopenia, peripheral edema, QT prolongation). 
 Severity of AEs 
Note, some hematology studies may choose to grade toxicity using alternatives to 
the CTCAE v4.03 (e.g., iwCLL criteria). When an alternative is used, please 
modify this section as needed. If using the CTCAE state: 
All non-hematologic adverse events will be graded according to the NCI 
Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. The 
CTCAE v4.03 is available at http://ctep.cancer.gov/reporting/ctc.html. 
If no CTCAE grading is available, the severity of an AE is graded as follows: 
• Mild (grade 1): the event causes discomfort without disruption of normal 
daily activities. 
• Moderate (grade 2): the event causes discomfort that affects normal daily 
activities. 
• Severe (grade 3): the event makes the patient unable to perform normal 
daily activities or significantly affects his/her clinical status. 
• Life-threatening (grade 4): the patient was at risk of death at the time of 
the event. 
• Fatal (grade 5): the event caused death. 
 Serious Adverse Events (SAEs) 
All SAEs, regardless of attribution, occurring from time of signed informed 
consent, through 30 days after the last administration of study drug, must be 
reported upon discovery or occurrence. 
An SAE is defined in regulatory terminology as any untoward medical occurrence 
that: 
• Results in death. 
If death results from (progression of) the disease, the disease should be 
reported as event (SAE) itself. 
• Is life-threatening. 
The patient was at risk of death at the time of the event; it does not 
refer to an event that hypothetically might have caused death if it were 
more severe. 
• Requires in-patient hospitalization or prolongation of existing 
hospitalization for ≥ 24 hours. 
IRB #: STU00073756-CR0005 Approved by NU IRB for use on or after 12/17/2019 through 12/16/2020.


Northwestern University 
 
                        
Study Number: NU12G11 
41 
 
Initial Version Date: 04/28/2013 
 
 
Amendment 8: 1/3/2019 
 
• Results in persistent or significant disability or incapacity. 
• Is a congenital anomaly/birth defect. 
• Is an important medical event. 
Any event that does not meet the above criteria, but that in the judgment of the 
investigator jeopardizes the patient, may be considered for reporting as a serious 
adverse event. The event may require medical or surgical intervention to prevent 
one of the outcomes listed in the definition of “Serious Adverse Event“.  
For example: allergic bronchospasm requiring intensive treatment in an 
emergency room or at home; convulsions that may not result in hospitalization; 
development of drug abuse or drug dependency. 
 Unanticipated Problems Involving Risks to Subject or Others 
A UPIRSO is a type of SAE that includes events that meet ALL of the following criteria: 
• 
Is unanticipated in terms of nature, severity, or frequency 
• 
Places the research subject or others at a different or greater risk of harm 
• 
Is deemed to be at least possibly related to participation in the study.    
 
9.3 
Adverse Event Reporting 
 Routine Reporting 
All routine adverse events, such as those that are expected, or are unlikely or 
definitely not related to study participation, are to be reported on the appropriate 
eCRF. Routine AEs will be reviewed by the Data and Safety Monitoring 
Committee (DSMC) according to the study’s phase and risk level, as outlined in 
the DSMP.  
 Determining if Expedited Reporting is Required 
This includes all events that occur within 30 days of the last dose of protocol 
treatment. Any event that occurs more than 30 days after the last dose of 
treatment and is attributed (possibly, probably, or definitely) to the agent(s) must 
also be reported accordingly. 
1) 
Identify the type of adverse event using the NCI CTCAE v 4.03. 
2) 
Grade the adverse event using the NCI CTCAE v 4.03. 
3) 
Determine whether the adverse event is related to the protocol therapy.   
Attribution categories are as follows: 
 
Definite: AE is clearly related to the study treatment. 
 
Probable: AE is likely related to the study treatment. 
 
Possible: AE may be related to the study treatment. 
 
Unlikely: AE not likely to be related to the study treatment. 
 
Unrelated: AE is clearly NOT related to the study treatment. 
4) 
Determine the prior experience of the adverse event. 
 
Expected events are those that have been previously identified as resulting from 
administration of the agent. An adverse event is considered unexpected, for 
IRB #: STU00073756-CR0005 Approved by NU IRB for use on or after 12/17/2019 through 12/16/2020.


Northwestern University 
 
                        
Study Number: NU12G11 
42 
 
Initial Version Date: 04/28/2013 
 
 
Amendment 8: 1/3/2019 
 
expedited reporting purposes only, when either the type of event or the severity of 
the event is not listed in: 
• 
the current protocol 
• 
the drug package insert 
• 
the current Investigator’s Brochure 
 
 Expedited Reporting of SAEs/Other Events 
 Reporting to the Northwestern University QAM/DSMC 
All SAEs must be reported to the assigned QAM within 24 hours of becoming 
aware of the event. Completion of the NU CRO SAE Form, provided as a 
separate document, is required. 
 
The completed form should assess whether or not the event qualifies as a 
UPIRSO. The report should also include: 
• Protocol description and number(s) 
• The patient’s identification number 
• A description of the event, severity, treatment, and outcome (if known) 
• Supportive laboratory results and diagnostics 
• The hospital discharge summary (if available/applicable) 
 
All SAEs will be reported to, and reviewed by, the DSMC at their next meeting. 
 Reporting to the Northwestern University IRB 
The following information pertains to the responsibilities of the lead site 
(Northwestern University). Additional participating sites should follow their 
local IRB guidelines for reporting to their local IRBs. 
• Any death of an NU subject that is unanticipated in nature and at least 
possibly related to study participation will be promptly reported to the NU 
IRB within 24 hours of notification.  
• Any death of an NU subject that is actively on study treatment (regardless 
of whether or not the event is possibly related to study treatment) 
• Any death of a non-NU subject that is unanticipated and at least possibly 
related and any other UPIRSOs will be reported to the NU IRB within 5 
working days of notification. 
• All other deaths of NU subjects not previously reported, other non-NU 
subject deaths that were unanticipated and unrelated, and any other SAEs 
that were not previously reported as UPIRSOs will be reported to the NU 
IRB at the time of annual continuing review. 
 
 Reporting to the FDA (to be done by QAM if applicable) 
The FDA will be notified within 7 calendar days of any SAE that is associated 
with study treatment, is unexpected, and is fatal or life-threatening. 
 
The FDA will be notified within 15 calendar days of any SAE that is associated 
with the study treatment, unexpected, and serious but not fatal or life-
IRB #: STU00073756-CR0005 Approved by NU IRB for use on or after 12/17/2019 through 12/16/2020.


Northwestern University 
 
                        
Study Number: NU12G11 
43 
 
Initial Version Date: 04/28/2013 
 
 
Amendment 8: 1/3/2019 
 
threatening. This includes any previous SAEs that were not initially deemed 
reportable, but are later determined to meet the criteria for reporting (i.e. by the 
DSMC). 
 
All other SAEs will be reported on an annual basis as part of the annual FDA 
report. 
 
 Reporting to AVEO Pharmacovigilance/Drug Safety and NCCN 
AVEO Pharmacovigilance/Drug Safety and NCCN must be informed of ALL 
SAE/suspected unexpected serious adverse reaction (SUSAR) reports within 24 
hours of first awareness. 
 
The Sponsor-Investigator must comply with any applicable requirements related 
to the reporting of SAEs involving his/her subjects to the IRB that approved the 
study. 
 
All SAEs should be recorded on the CRO SAE Form and sent to AVEO and 
NCCN: 
 
• AVEO SAE reports should be sent to Parexel GPPG at 
AVEOsafety@parexel.com.  If submission via email is not possible or 
delayed then submission via fax (NA: +1-781-434-5957) is acceptable. 
 
Occasionally, AVEO Pharmacovigilance/Drug Safety may contact the 
reporter for additional information, clarification, or current status of the 
subject for whom the adverse event was reported. 
 
• National Comprehensive Cancer Network (NCCN) 
Fax: (215)358-7699 
Email: orpreports@nccn.org 
 
 Safety Reporting Requirements for IND Holders 
For Investigator Sponsored IND Studies there are some additional reporting 
requirements for the FDA in accordance with the guidance set forth in 21 CFR 
312.32.  Sponsor-investigators of studies conducted under an IND must comply 
with the following safety reporting requirements: 
 
 Expedited IND Safety Reports 
The Sponsor-Investigator is required to report all serious, unexpected and 
related adverse events directly to the FDA on a MEDWATCH Form 
3500A (Appendix E) within 7 (if fatal or life-threatening) or 15 calendar 
days of first awareness, as described below.   
 
IRB #: STU00073756-CR0005 Approved by NU IRB for use on or after 12/17/2019 through 12/16/2020.


Northwestern University 
 
                        
Study Number: NU12G11 
44 
 
Initial Version Date: 04/28/2013 
 
 
Amendment 8: 1/3/2019 
 
AVEO Pharmacovigilance/Drug Safety  and  NCCN must be informed of 
ALL SAEs on a MEDWATCH Form 3500A within 24 hours of first 
awareness, whether or not they are considered related to the 
investigational agent(s)/protocol intervention (21 CFR 312.64). 
 
9.4 
IND Annual Reports 
In accordance with the regulation 21 CFR 312.33, the Sponsor-Investigator shall 
within 60 days of the anniversary date that the IND went into effect submit a brief 
report of the progress of the investigation.  Please refer to Code of Federal 
Regulations, 21 CFR 312.33 for a list of the elements required for the annual 
report.  All IND annual reports submitted to the FDA by the Sponsor-Investigator 
should be copied to AVEO.  Copies of such reports should be submitted to AVEO 
via NCCN.  
 
10 
CORRELATIVES/SPECIAL STUDIES 
 
Correlative Samples - Details for Lab Manual  
 
Correlative study (sample 
type) 
e.g. Pharmacokinetics 
(blood) 
Tissue 
Mandatory or Optional 
Optional 
Timing (+/- windows) 
Retrospective 
Volume Needed (blood only) 
n/a 
Tube type needed (blood 
only) 
n/a 
Tissue thickness and/or # 
slides (tissue only) 
10 FFPE slides cut at 5um 
Processing center (e.g. PCF-
CTU) 
PCF-CTU 
Sample handling/processing 
instructions 
 
Shipping/delivery info  
All samples will be analyzed  
 
 
Storage needs 
Samples can be stored at RT and batch delivered 
to the Matei Lab. 
Analysis center 
Matei Lab 
Lurie Medical Research Center 
303 E Superior St, Suite 4-220 
Chicago, IL 60611 
Assay methodology 
IHC 
 
10.1 Sample Collection Guidelines 
IRB #: STU00073756-CR0005 Approved by NU IRB for use on or after 12/17/2019 through 12/16/2020.


Northwestern University 
 
                        
Study Number: NU12G11 
45 
 
Initial Version Date: 04/28/2013 
 
 
Amendment 8: 1/3/2019 
 
 Tissue Samples 
Archival tissue samples from all patients enrolled in the study will be requested.  
Ten FFPE slides with tissue cut at approximately 5um thick will be used for IHC. 
 
 NGS 
Collection of existing reports detailing genomic testing (Tempus, Foundation 
One, Charis, other).  No additional testing will be obtained, but where data is 
available, it will be collected and analyzed.  Correlate presence of detectable 
molecular alterations (mutations, deletions, amplifications, fusion) in the 
VEGF/PDGF pathway with response to treatment (CR, PR, SD, PD). 
 
10.3 Assay Methodology 
Standard staining techniques will be used to measure the expression of proteins that 
play a role in VEGF signaling and other relevant oncogenic pathways (VEGF, 
VEGFR1, 2, 3, PDGFR α and β).  Protein expression levels measured by IHC will 
be correlated with response to treatment (CR, PR, SD, PD). 
 
11 STUDY MANAGEMENT 
11.1 Institutional Review Board (IRB) Approval and Consent  
It is expected that the IRB will have the proper representation and function in 
accordance with federally mandated regulations. The IRB should approve the 
consent form and protocol. 
 
In obtaining and documenting informed consent, the investigator should comply 
with the applicable regulatory requirement(s), and should adhere to Good Clinical 
Practice (GCP) and to ethical principles that have their origin in the Declaration 
of Helsinki. 
 
 
Before recruitment and enrollment onto this study, the patient will be given a full 
explanation of the study and will be given the opportunity to review the consent 
form. Each consent form must include all the relevant elements currently required 
by the FDA Regulations and local or state regulations. Once this essential 
information has been provided to the patient and the investigator is assured that 
the patient understands the implications of participating in the study, the patient 
will be asked to give consent to participate in the study by signing an IRB 
approved consent form. 
 
Prior to a patient’s participation in the trial, the written informed consent form 
should be signed and personally dated by the patient and by the person who 
conducted the informed consent discussion.  
11.2 Amendments 
The Principal Investigator will formally initiate all amendments to the protocol 
and/or informed consent. All amendments will be subject to the review and 
approval of the appropriate local, institutional, and governmental regulatory 
bodies, as well as by Janssen Scientific Affairs. Amendments will be distributed 
IRB #: STU00073756-CR0005 Approved by NU IRB for use on or after 12/17/2019 through 12/16/2020.


Northwestern University 
 
                        
Study Number: NU12G11 
46 
 
Initial Version Date: 04/28/2013 
 
 
Amendment 8: 1/3/2019 
 
by the lead institution (Northwestern) to all affiliate sites upon approval by the 
Northwestern University IRB. 
11.3 Registration Procedures 
For potential patients for the phase I portion of this study, study teams are asked 
to inform the QAM of the date and time that the patient will need to be registered 
(croqualityassurance@northwestern.edu).   
 
BEFORE a patient can be treated on study, please complete and submit the 
following items to confirm eligibility and receive an identification number: 
• Patient’s signed and dated informed consent form (upload to NOTIS and 
keep original hard copy in a secure location/study chart) 
• Eligibility checklist (signed and dated by the treating physician – upload 
to NOTIS) 
• Eligibility eCRF (complete in NOTIS) 
• Copy of the pathology report (upload to NOTIS) 
 
The QAM will review all source documentation required to confirm eligibility 
that is readily available in the patient’s electronic medical record (EMR).  Any 
information that is not available in the EMR must be de-identified and emailed to 
the QAM. Once the QAM confirms the patient is eligible, he or she will register 
the patient, assign a subject identification number, provide a cohort assignment, 
and send a confirmation of registration to involved personnel. Registration will 
then be complete and the patient may begin study treatment.  
 
11.4 Data Submission 
Once a subject is confirmed and registered to the study, eCRFs should be 
submitted according to the detailed data submission guidelines (provided in a 
separate document).  Generally, all data for phase I patients during the time period 
patients are evaluated for Dose Limiting Toxicities (DLTs) must be submitted on 
a weekly basis.   Generally, for all phase II patients, data are due at the end of 
every cycle.   
 
This is a general template.  Data Submission language can be revised as make 
sense for each protocol.  A detailed data submission guideline must be included as 
a separate document for all NU IITs determined to require high or moderate level 
intensity monitoring.  To develop your data submission guideline, contact 
croqualityassurance@northwestern.edu. 
11.5 Instructions for Participating Sites 
Before the study can be initiated at any site, the following documentation must be 
provided to the Clinical Research Office at Northwestern University: 
• Signed and completed Letter of Invitation to participate in the study. 
• Signed copy of Northwestern University’s Data Monitoring Committee 
policy pertaining to data submission. 
IRB #: STU00073756-CR0005 Approved by NU IRB for use on or after 12/17/2019 through 12/16/2020.


Northwestern University 
 
                        
Study Number: NU12G11 
47 
 
Initial Version Date: 04/28/2013 
 
 
Amendment 8: 1/3/2019 
 
• Draft informed consent form should for review/approval prior to submission 
to the local IRB 
• A copy of the official IRB approval letter for the protocol and informed 
consent.  
• CVs and medical licensure for the local PI and any sub-investigators who 
will be involved in the study at the site. 
• Form FDA 1572 appropriately filled out and signed with appropriate 
documentation. 
 
Additional activities may be required prior to site activation (i.e. contract 
execution, study-specific training). Full requirements will be outlined in a memo 
upon receipt of the signed Letter of Invitation. 
 
11.6 Data Management and Monitoring/Auditing 
This study will be conducted in compliance with the Data Safety Monitoring Plan 
(DSMP) of the Robert H. Lurie Comprehensive Cancer Center of Northwestern 
University (please refer to Appendices for additional information). The level of 
risk attributed to this study requires High Risk Monitoring as outlined in the 
DSMP. The assigned QAM, with oversight from the Data Monitoring Committee, 
will monitor this study in accordance with the study phase and risk level. Please 
refer to the Appendices for additional data submission instructions. 
 
11.7 Adherence to the Protocol 
Except for an emergency situation in which proper care for the protection, safety, 
and well-being of the study patient requires alternative treatment, the study shall 
be conducted exactly as described in the approved protocol.  
 
 Emergency Modifications 
Investigators may implement a deviation from, or a change of, the protocol to 
eliminate an immediate hazard(s) to trial subjects without prior IRB approval.  
 
For any such emergency modification implemented, an IRB modification form 
must be completed within 5 business days of making the change, and the QAM 
must be notified within 24 hours of such change.  
 
 Other Protocol Deviations 
All other deviations from the protocol must be reported to the assigned QAM 
using the appropriate form. 
 
A protocol deviation is any unplanned variance from an IRB approved protocol 
that:  
• Is generally noted or recognized after it occurs. 
• Has no substantive effect on the risks to research participants. 
• Has no substantive effect on the scientific integrity of the research plan or the 
value of the data collected. 
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• Did not result from willful or knowing misconduct on the part of the 
investigator(s).  
 
A protocol deviation may be considered an instance of Promptly Reportable Non-
Compliance (PRNC) if it: 
• Has harmed or increased the risk of harm to one or more research participants. 
• Has damaged the scientific integrity of the data collected for the study. 
• Results from willful or knowing misconduct on the part of the investigator(s). 
• Demonstrates serious or continuing noncompliance with federal regulations, 
State laws, or University policies. 
 
11.8 Investigator Obligations 
The Principal Investigator is responsible for the conduct of the clinical trial at the site in 
accordance with Title 21 of the Code of Federal Regulations and/or the Declaration of 
Helsinki. The PI is responsible for personally overseeing the treatment of all study 
patients. The PI must assure that all study site personnel, including sub-investigators and 
other study staff members, adhere to the study protocol and all FDA/GCP/NCI 
regulations and guidelines regarding clinical trials both during and after study 
completion. 
 
The Principal Investigator at each institution or site will be responsible for assuring that 
all the required data will be collected, entered onto the appropriate eCRFs, and submitted 
within the study-specific timeframes. Periodically, monitoring visits may be conducted 
and the Principal Investigator will provide access to his/her original records to permit 
verification of proper entry of data. The study may also be subject to routine audits by the 
Audit Committee, as outlined in the DSMP.  
 
11.9 Publication Policy 
All potential publications and/or data for potential publications (e.g. manuscripts, 
abstracts, posters, clinicaltrials.gov releases) must be approved in accordance with the 
policies and processes set forth in the Lurie Cancer Center DSMP. For trials that require 
high intensity monitoring, the assigned QAM will prepare a preliminary data summary 
(to be approved by the DSMC) no later than 3 months after the study reaches its primary 
completion date (the date that the final subject is examined or receives an intervention for 
the purposes of final data collection for the primary endpoint). If the investigator’s wish 
to obtain DSMC-approved data prior to this point (or prior to the point dictated by study 
design), the PI must send a written request for data to the QAM which includes 
justification. If the request is approved, data will be provided no later than 4 weeks after 
this request approval. The data will be presented to the DSMC at their next available 
meeting, and a final, DSMC-approved dataset will be released along with any DSMC 
decisions regarding publication. The investigators are expected to use only DSMC-
approved data in future publications. The investigators should submit a copy of the 
manuscript to the biostatistician to confirm that the DSMC-approved data are used 
appropriately.  Once the biostatistician gives final approval, the manuscript may be 
submitted to external publishers. 
 
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12.0 
REFERENCES 
1. Siegel R, et al.  Cancer statistics, 2012.  CA Cancer J Clin 2012; 62:10. 
2. Peng L, et al.  Topotecan for ovarian cancer.  Cochrane Database Syst Rev 2008; :CD005589. 
3. Nakamura K, et al.  KRN951, a highly potent inhibitor of vascular endothelial growth factor 
receptor tyrosine kinases, has antitumor activities and affects vascular properties.  Cancer Res 
2006; 66(18):9134. 
4. Pal S, et al.  Tivozanib: current status and future directions in the treatment of solid tumors.  
Expert Opin Investig Drugs 2012 September 26 [Epub ahead of print]. 
5. Gomez-Rivera F, et al.  The tyrosine kinase inhibitor, AZd2171, inhibits vascular endothelial 
growth factor receptor signaling and growth of anaplastic thyroid cancer in an orthotopic nude 
mouse model.  Clin Cancer Res 2007; 13(15):4519. 
6. Tivozanib (AV-951) Investigator’s Brochure, Version 9.2.  AVEO Pharmaceuticals, Inc.  May 
9, 2012. 
7. Eskens F, et al.  Biologic and clinical activity of tivozanib (AV-951) a selective inhibitor of 
VEGF receptor-1, -2, and -3 tyrosine kinases, in a 4-week-on, 2-week-off schedule in patients 
with advanced solid tumors.  Clin Cancer Res 2011;17(22):7156. 
8. Eskens F, et al.  A phase Ib, open-label, dose escalation study of tivozanib and FOLFOX6 in 
patients with advanced gastrointestinal tumors.  ASCO Meeting abstract 2011;29(4 
supplement):549. 
9. Mayer E, et al.  Combination of tivozanib (AV-951) with weekly paclitaxel for metastatic 
breast cancer: results of a phase I study.  ASCO Meeting Abstract 2011;29(15 supplement):1092. 
10. Nosov D, et al.  Final analysis of the phase II randomized discontinuation trial of tivozanib 
versus placebo in patients with renal cell carcinoma.  ASCO Meeting Abstract 2011; 29(15 
supplement):4550. 
11. Motzer R, et al.  Tivozanib versus sorafenib as initial targeted therapy for patients with 
advanced renal cell carcinoma: Results from a phase III randomized, open-label, multicenter 
trial.  ASCO Meeting Abstract 2012;30(15 Supplement):4501. 
12. Ferrara N, et al.  The role of vascular endothelial growth factor in pathological angiogenesis.  
Breast Cancer Res Treat 195;36(2):127. 
13. Kim K, et al.  Inhibition of vascular endothelial growth factor-induced angiogenesis 
suppresses tumor growth in vivo.  Nature 1993;362(6423):841. 
14. Valtola R, et al. VEGFR-3 and its ligand VEGF-C are associated with angiogenesis in breast 
cancer. Am J Pathol 1999;154:1381. 
15. Rustin GJS, Quinn M, Thigpen T, DuBois A, et al. Re: new guidelines to evaluate the 
response to treatment in solid tumors (ovarian cancer).  J Natl Cancer Inst  2004; 96(6):487-488, 
doi: 10.1092/jnci/kjh081.  
16. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, et al. New response evaluation criteria 
in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009 Jan;45(2):228-47. 
doi: 10.1016/j.ejca.2008.10.026. 
17. Vergote I, Rustin GJ, Eisenhauer EA, Kristensen GB, et al. Re: new guidelines to evaluate 
the response to treatment in solid tumors [ovarian cancer]. Gynecologic Cancer Intergroup. J 
Natl Cancer Inst. 2000 Sep 20;92(18):1534-5. 
18. Simon R (1989). Optimal two-stage designs for phase II clinical trials, Controlled Clinical 
Trials 10: 1-10. 
19.  Jung SH, Lee TY, Kim KM, George S (2004). Admissible two-stage designs for phase II 
cancer clinical trials, Statistics in Medicine 23: 561-569. 
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12 APPENDICES  
 
12.1 Appendix A 
Performance Status Criteria 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
1 
Symptoms, but ambulatory.  
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). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 
 
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12.2 Appendix B 
Cytochrome P450 (CYP3A4) Strong/moderate 
Inducers/Inhibitors 
Investigators should consult a frequently updated drug information reference (see below) for a 
list of strong inducers and prohibitors.  
Flockhard DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University 
School of Medicine (2007). http://medicine.iupui.edu/clinpharm/ddis/table.asp. 
As this list is constantly evolving, if a medication is incorrectly documented as prohibited in this 
protocol, documentation from the site pharmacist to the contrary will be acceptable for the 
purposes of registration. 
 
 
 
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12.3 Appendix C: Management of Hypertension 
 
RECOMMENDED MANAGEMENT FOR 
TIVOZANIB HYDROCHLORIDE-RELATED HYPERTENSION 
 
Figure 1 provides a guideline for treatment of hypertension (HTN); however, changes may be 
made at the discretion of the treating physician.  
 
 
 
 
RECOMMENDED ANTI_HYPERTENSIVE MEDICATIONS 
Agent 
Initial Dose 
Intermediate Dose 
Maximum Dose 
Dihydropyridine (DHP) Calcium Channel Blockers 
Nifedipine XL 
30 mg po qd 
60 mg po qd 
90 mg po qd 
Amlodipine 
2.5 mg po qd 
5 mg po qd 
10 mg po qd 
Felodipine 
2.5 mg po qd 
5 mg po qd 
10 mg po qd 
Angiotensin Converting Enzyme (ACE) Inhibitors 
Captopril 
12.5 mg po tid 
25 mg po tid 
50 mg po tid 
Enalapril 
5 mg po qd 
10–20 mg po qd 
40 mg po qd 
Ramipril 
2.5 mg po qd 
5 mg po qd 
10 mg po qd 
Lisinopril 
5 mg po qd 
10–20 mg po qd 
40 mg po qd 
Fosinopril 
10 mg po qd 
20 mg po qd 
40 mg po qd 
Perindopril 
4 mg po qd 
None 
8 mg po qd 
Quinapril 
10 mg po qd 
20 mg po qd 
20 mg po qd 
Angiotensin II Receptor Blockers 
Losartan 
25 mg po qd 
50 mg po qd 
100 mg po qd 
Candesartan 
4 mg po qd 
8–16 mg po qd 
32 mg po qd 
Ibresartan 
75 mg po qd 
150 mg po qd 
300 mg po qd 
Telmisartan 
40 mg po qd 
None 
80 mg po qd 
Valsartan 
80 mg po qd 
None 
160 mg po qd 
po = oral administration; qd = once daily; tid = three times daily 
Adapted from Kollmannsberger C, et al, CUAJ. 2007;Vol 1 (Issue 2 Suppl):S41–54. 
 
Management of Hypertension 
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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 Figure 1 (Appendix C). 
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 C, 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 then the previous 
regimen, this would be considered Grade 3 HTN. 
Hypertension will be considered controlled if the following criteria are met: Diastolic blood 
pressure is reduced to less than 100 mmHg within 2 weeks of the initiation of anti-hypertensive 
treatment, confirmed by two consecutive blood pressure measurements at least 24 hours apart. 
Diastolic blood pressure does not increase by more than 20 mmHg subsequent to the start of anti-
hypertensive treatment. 
If subjects require a delay of >2 weeks for management of hypertension, discontinue protocol 
therapy. Subjects may have up to 2 drugs for management of hypertension prior to any dose 
reduction in tivozanib. 24-48 hours should elapse between modifications of antihypertensive 
therapy. 
 
 
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12.4 Appendix D 
CTCAE v.4.03 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf 
 
 
 
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12.5 Appendix E: Summary of Changes 
Amendment 5 – February 21, 2017 
Section(s) Affected 
Prior Version 
Amendment 5 
Changes 
Rationale 
Cover Page 
Emily Berry, MD, 
Kristina Mori, MD & 
Abigail Winder, MD 
listed as Sub-
Investigators 
Removed Emily 
Berry, MD, Kristina 
Mori, MD and Abigail 
Winder, MD as Sub-
Investigators and 
replaced with Wilberto 
Nieves-Neira, MD, 
Shohreh Shahabi, MD, 
Margaux Kanis, MD, 
Anna Strohl, MD, 
Brandon Seagle, MD, 
Valerie Nelson, MD, 
Barbara Buttin MD, 
and LaToya Perry, 
MD 
Administrative 
Study Drug 
Intervention(s):  
Tivozanib 
Hydrochloride, IND#: 
117703 
IND Number and IND 
Holder listed as their 
own categories. 
To adhere to NU 
protocol template 
“Protocol” 
Removed “Protocol” 
from cover page 
To adhere to NU 
protocol template 
Co-Investigator 
Sub-Investigator 
To adhere to NU 
protocol template 
Statistician 
Biostatistician 
To adhere to NU 
protocol template 
Funding Organization 
Funding Source 
To adhere to NU 
protocol template 
Table of Contents 
N/A 
“Table of Contents” 
title added 
To adhere to NU 
protocol template 
List of Abbreviations N/A 
Added “List of 
Abbreviations”  
To adhere to NU 
protocol template 
Study Schema 
N/A 
Study Schema was 
added  
To adhere to NU 
protocol template 
Study Summary 
“Synopsis” title 
“Study Summary” title To adhere to NU 
protocol template 
Diagnosis and Main 
Inclusion Criteria 
Diagnosis and Key 
Eligibility Criteria 
To adhere to NU 
protocol template 
“Analysis Summary” 
Title 
“Statistical 
Methodology” title 
To adhere to NU 
protocol template 
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Section 1.0 
Introduction – 
Background & 
Rationale 
Title “Background & 
Rationale” 
Title “Introduction – 
Background & 
Rationale” 
To adhere to NU 
protocol template 
Section 1.2.2 
Clinical Studies 
“…pharmacodynamics 
(PD) studies were also 
performed…” 
“…pharmacodynamics 
studies were also 
performed…” 
Abbreviation of 
“PD” indicates 
“progressive 
disease”, not 
pharmacodynamic
s. 
Section 3.0 Patient 
Selection 
N/A 
NU Template 
language inserted for 
clarification of target 
population, 
recruitment 
approximation, PI 
contact information. 
To adhere to NU 
protocol template 
Single-site study 
Multi-site study 
including 
Northwestern 
Medicine Cancer 
Center Warrenville 
and the Northwestern 
Medicine Cancer 
Center Delnor and 
Northwestern Lake 
Forest Hospital. 
Study will include 
additional sites. 
3.1.1 Inclusion 
Criteria 
“Patients must have 
recurrent or persistent, 
platinum resistant….” 
 
“…within 6 months of 
completing adjuvant, 
platinum-based 
chemotherapy. “ 
“Patients must have 
recurrent or persistent 
platinum resistant or 
refractory…” 
 
“…within 6 months of 
completing platinum-
based chemotherapy. “ 
“Refractory” was 
included in criteria 
to clarify the 
patient population 
allowed. 
 
“Adjuvant” was 
removed from 
inclusion criteria 
to clarify that any 
prior platinum-
based 
chemotherapy is 
included. 
3.1.3 Inclusion 
Criteria 
“Patients with 
measurable disease 
must have at least one 
“target lesion” to be 
used to assess response 
“Patients with 
measurable disease 
must have at least one 
target lesion as 
defined by RECIST 
Updated text to 
use RECIST 1.1 
and clarified 
sentence. 
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on this protocol as 
defined by RECIST.” 
1.1 to be used to 
assess response on this 
protocol.” 
3.1.5 Inclusion 
Criteria 
N/A 
Added: “Note: Use of 
bevacizumab as 
maintenance therapy 
after initial adjuvant 
platinum-based 
chemotherapy is 
allowed so long as 
platinum-resistant 
recurrence occurred 
subsequent to a 
separate platinum-
based regimen AND 
more than 6 months 
after completion of 
bevacizumab 
maintenance.” 
Clarification of 
bevacizumab as 
prior therapy for 
patient eligibility 
3.1.7 Inclusion 
Criteria 
“Patients must meet 
pre-entry requirements 
as specified in section 
8.2” 
Removed criteria 
Section 8.2 was 
removed. 
N/A 
Added criteria 
“Patients must be 
willing and able to 
complete all study 
procedures” 
To adhere to NU 
protocol template 
3.1.8 Inclusion 
Criteria 
List of organ and bone 
marrow function 
requirements for 
eligibility 
Converted list of 
organ and bone 
marrow function 
requirements into a 
table 
To adhere to NU 
protocol template 
 
List of organ and bone 
marrow function 
requirements listed in 
exclusion criteria 
List of organ and bone 
marrow function 
requirements moved to 
inclusion criteria 
 
All criteria was altered 
to define adequate 
function 
To adhere to NU 
protocol template 
 
BOTH total bilirubin > 
ULN AND AST or 
ALT > ULN 
Also excluded are 
patients with 
elevations in BOTH 
total bilirubin > ULN 
For clarification 
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AND AST or ALT > 
ULN 
 
3.1.10 Inclusion 
Criteria 
Language regarding 
adequate contraception. 
Replaced with NU 
template language 
regarding females of 
child-bearing potential 
(FCOBP) and males to 
agree to use adequate 
contraception 
To adhere to NU 
protocol template 
 
3.1.11 Inclusion 
Criteria 
N/A 
FOCBP must have a 
negative pregnancy 
test within 7 days 
prior to registration on 
study. 
Confirm 
pregnancy before 
study therapy. 
3.1.12 Inclusion 
Criteria 
N/A 
Patients must have the 
ability to understand 
and the willingness to 
sign a written 
informed consent prior 
to registration on 
study. 
To adhere to NU 
protocol template 
 
3.2.1 Exclusion 
Criteria 
“Age Patients < 18 
years of age are 
excluded” 
Removed  
Patient age 
requirements 
already stated in 
Inclusion Criteria 
3.1.9 
“Patients who have had 
previous treatment with 
tivozanib” 
“Patients who have 
had previous treatment 
with tivozanib are 
excluded.” 
Clarification 
3.2.2 Exclusion 
Criteria 
Previously listed under 
3.2.4 “symptomatic left 
ventricular dysfunction 
or baseline left 
ventricular ejection 
fraction (LVEF) by 
multigated acquisition 
scan (MUGA) or 
echocardiogram 
(ECHO) of ≤ lower 
limit of institutional 
normal (LLN)” 
Made a standalone 
criteria: “Patients with 
symptomatic left 
ventricular 
dysfunction or 
baseline left 
ventricular ejection 
fraction (LVEF) my 
multigated acquisition 
scan (MUGA) or 
echocardiogram 
(ECHO) of ≤ 50% are 
not eligible.” 
LVEF drop is a 
known side effect 
of tivozanib.  
Standalone criteria 
was added so that 
there is 
documentation of 
LVEF for eligibility. 
3.2.3 Exclusion 
Criteria 
Previously listed under 
3.2.4 “Uncontrolled 
Made a standalone 
criteria: “Patients with 
Because patient 
must meet certain 
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Amendment 8: 1/3/2019 
 
hypertension: systolic 
blood pressure of 
>140mmHg or diastolic 
blood pressure of 
>90mmHg documented 
on 2 consecutive 
measurements taken at 
least 24 hours apart” 
uncontrolled 
hypertension as 
defined as Systolic 
blood pressure of 
>140mmHg or 
diastolic blood 
pressure of >90mmHg 
documented on 2 
consecutive 
measurements taken at 
least 24 hours apart 
are not eligible.” 
criteria for 
eligibility, 
hypertension is 
made a standalone 
criteria. 
3.2.4 Exclusion 
Criteria 
“Significant 
cardiovascular disease, 
including:” 
“Patients with 
significant 
cardiovascular disease 
are excluded, 
including:” 
For clarification 
 
3.2.5 Exclusion 
Criteria 
“Central nervous 
system metastases” 
“Patients with central 
nervous system 
metastases are 
excluded” 
For clarification 
 
3.2.6 Exclusion 
Criteria 
“Non-healing wound, 
bone fracture, or skin 
ulcer” 
“Any patient with a 
current non-healing 
wound, bone fracture, 
or skin ulcer is 
excluded”  
For clarification 
 
3.2.7 Exclusion 
Criteria 
N/A 
Added exclusion 
criteria restricting 
treatment with drugs 
known to be strong 
inhibitors or inducers 
of isoenzyme 
CYP3A4 including 
herbal medications 
Drugs known to be 
strong inhibitors or 
inducers of 
CYP3A4 are 
restricted on this 
study therapy. 
3.2.10 Exclusion 
Criteria 
“Corrected QT interval 
(QTc) of > 480 msec 
using Bazett’s formula.” 
“Patients must not 
have a corrected QT 
interval (QTc) of > 
480 msec using 
Bazett’s formula.” 
For clarification 
3.2.11 Exclusion 
Criteria 
“Radiotherapy or minor 
surgical procedure 
within 2 weeks, or 
major surgical 
procedure within 4 
weeks prior to 
administration of first 
“Patients who have 
had radiotherapy or 
minor surgical 
procedure within 14 
days, or major 
surgical procedure 
within 28 days prior 
For clarification 
and adherence to 
NU template. 
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dose of study drug; 
inadequate recovery 
from prior surgical 
procedure.” 
to administration of 
first dose of study 
drug are not eligible; 
patients with 
inadequate recovery 
from prior surgical 
procedure are also not 
eligible.” 
3.2.12 Exclusion 
Criteria 
N/A 
Added criteria 
excluding: “Patients 
with active infection 
requiring antibiotics 
are not eligible (with 
the exception of 
uncomplicated UTI 
and uncomplicated 
respiratory tract 
infections).” 
Patients with 
infections are not 
eligible for the 
study treatment. 
3.2.13 Exclusion 
Criteria 
N/A 
Added criteria 
excluding: “Patients 
may not have had any 
prior systemic therapy 
≤ 21 days prior to 
registration for 
treatment of ovarian 
cancer.” 
A 21 day washout 
period is necessary 
before beginning 
this study therapy.  
3.2.14 Exclusion 
Criteria 
N/A 
Addition of criteria 
excluding: “Patients 
who have received 
investigational or 
licensed drugs that 
target vascular 
endothelial growth 
factor [VEGF] or 
VEGF 
receptors/pathways 
(such as bevacizumab, 
sorafenib, pazopanib, 
sunitinib, axitinib, 
cabozantinib, etc.) for 
the treatment of 
recurrent cancer are 
not eligible. 
Exceptions: prior 
treatment with 
bevacizumab in the 
Clarify patients 
who are excluded 
from study due to 
previous 
investigational or 
licensed therapy. 
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up-front or 
maintenance setting is 
allowed, provided the 
patient had a favorable 
response to 
bevacizumab. 
Favorable response is 
defined as having had 
a disease free interval 
of >6 months 
following completion 
of a bevacizumab-
containing regimen. If 
questions, contact the 
PI.” 
3.2.15 Exclusion 
Criteria 
Referenced CTCAE 
Version 4.0 
Updated to reference 
CTCAE Version 4.03 
Updated to utilize 
current version of 
CTCAE (Version 
4.03) 
3.2.16 Exclusion 
Criteria 
Referenced CTCAE 
Version 4.0 
Updated to reference 
CTCAE Version 4.03 
Updated to utilize 
current version of 
CTCAE (Version 
4.03) 
3.2.17 Exclusion 
Criteria 
Non metastatic prostate 
cancer listed in 
restriction of currently 
active primary 
malignancy 
Non metastatic 
prostate cancer 
removed from list of 
currently active 
primary malignancy 
Patient population 
is female and 
would not have 
non metastatic 
prostate cancer 
3.2.18 Exclusion 
Criteria 
“Pregnant or lactating 
females” 
“Pregnant or lactating 
females are excluded” 
For clarification 
 
 
 
 
4.0 Patient 
Registration 
Instructions outlining 
patient registration 
procedures. 
Section was replaced 
with NU template 
language found in 
section 10.  
To adhere to NU 
protocol template 
 
4.1 Overview 
N/A 
Included an overview 
of treatment plan that 
is outlined in the NU 
template. 
To adhere to NU 
protocol template 
 
4.2 Study Drug 
Administration: 
Tivozanib 
Details on study drug 
administration (other 
names, classification, 
mechanisms of action, 
molecular formula and 
weight, chemical name, 
approximate solubility, 
Information was 
moved to Section 6 
Drug Information to 
adhere to NU template 
format 
To adhere to NU 
protocol template 
 
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Northwestern University 
 
                        
Study Number: NU12G11 
63 
 
Initial Version Date: 04/28/2013 
 
 
Amendment 8: 1/3/2019 
 
route of administration, 
dose to be administered) 
4.2.4 Dosing 
Parameters 
Previously listed under 
management of 
hematologic toxicity  
Moved to Study drug 
administration section 
Management of 
hematologic 
toxicity section 
was removed.  
This information 
was retained and 
moved to Study 
Drug 
Administration 
section. 
4.3.1.4 
Premedications for 
Study Drug-Related 
Toxicities 
N/A 
Clarified that weak 
CYP3A4 inducers or 
inhibitors are to be 
used with caution 
For clarification 
4.3.2.3 General 
Concomitant 
Medication and 
Supportive Care 
Guidelines 
N/A 
Added note: “As this 
list is constantly 
evolving, if a 
medication is 
incorrectly 
documented as 
prohibited in this 
protocol, 
documentation from 
the site pharmacist to 
the contrary will be 
acceptable for the 
purposes of 
registration.” 
Addition of note to 
clarify use of 
CYP3A4 inducers 
of inhibitors. 
4.3.2.4 
Premedications for 
Study Drug-Related 
Toxicities 
Previously listed under 
4.3.3 The following 
medications/treatments 
are permitted during the 
study treatment 
Moved to list under 
prohibited medications 
For clarification – 
so all information 
on prohibited 
medications is in 
one place. 
4.3.2.6 
Premedications for 
Study Drug-Related 
Toxicities 
Previously listed under 
4.7.3 Management of 
Hematologic Toxicity 
Moved to list under 
prohibited medications 
For clarification – 
so all information 
on prohibited 
medications is in 
one place. 
4.3.2.7 
Premedications for 
Study Drug-Related 
Toxicities 
Previously listed under 
4.7.3 Management of 
Hematologic Toxicity 
Moved to list under 
prohibited medications 
For clarification – 
so all information 
on prohibited 
medications is in 
one place. 
IRB #: STU00073756-CR0005 Approved by NU IRB for use on or after 12/17/2019 through 12/16/2020.


Northwestern University 
 
                        
Study Number: NU12G11 
64 
 
Initial Version Date: 04/28/2013 
 
 
Amendment 8: 1/3/2019 
 
4.3.2.8 General 
Concomitant 
Medication and 
Supportive Care 
Guidelines 
Previously listed under 
4.7.3 Management of 
Hematologic Toxicity 
Moved to list under 
prohibited medications 
For clarification – 
so all information 
on prohibited 
medications is in 
one place. 
4.3.3.1 The 
following 
medications/treatmen
ts are permitted 
during the study 
treatment 
“Full dose oral 
anticoagulants (such as 
warfarin, and other 
similar agents; with 
target INR 2-3) and/or 
anticoagulation with 
low molecular weight 
heparin or 
unfractionated heparin 
administered 
subcutaneously…” 
“Full dose oral 
anticoagulants and/or 
anticoagulation with 
low molecular weight 
heparin or 
unfractionated heparin 
administered 
subcutaneously…” 
Removed outdated 
examples in order 
to include all 
current 
anticoagulants 
4.4 Duration of 
Therapy 
Section title: “Duration 
of Treatment and 
Follow Up” 
Section Title: 
“Duration of Therapy” 
Split up 
explanation of 
duration of 
treatment and 
follow up to 
adhere to NU 
template. 
“In the absence of 
treatment delays due to 
adverse event(s), 
treatment may continue 
until one of the 
following criteria 
applies: 
• Disease progression, 
• Intercurrent illness 
that prevents further 
administration of 
treatment, 
• Unacceptable adverse 
event(s), 
• Patient decides to 
withdraw from the 
study, or 
• General or specific 
changes in the 
patient's condition 
render the patient 
unacceptable for 
further treatment in 
“Patients may 
continue to receive 
cycles of treatment 
until any of the 
following occur: 
• Disease progression 
• Development of an 
inter-current illness 
that prevents further 
administration of 
treatment 
• Unacceptable 
adverse event(s) 
• Patient decides to 
withdraw from 
either study 
treatment or the as a 
whole study 
• The treating 
investigator 
determines that the 
patient should be 
taken off treatment 
Replaced 
description of 
duration of therapy 
with NU template 
language. 
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Northwestern University 
 
                        
Study Number: NU12G11 
65 
 
Initial Version Date: 04/28/2013 
 
 
Amendment 8: 1/3/2019 
 
the judgment of the 
investigator.” 
for any reason (i.e. 
changes in 
condition, inability 
to comply with 
study treatment or 
procedures)” 
4.5 Duration of 
Follow Up 
“Subjects will be 
followed for every 3 
months for 2 years and 
then every 6 months for 
3 years after removal 
from study or until 
death, whichever occurs 
first.  Subjects removed 
from study for 
unacceptable adverse 
event(s) will be 
followed until 
resolution or 
stabilization of the 
adverse event.” 
“Patients will return 
for an end of 
treatment visit within 
30 days (±3 days) of 
the last dose of study 
treatment. 
 
Subjects will be 
followed for every 3 
months for 2 years and 
then every 6 months 
for 3 years after 
removal from study or 
until death, whichever 
occurs first.  Subjects 
will be monitored for 
survival for this 5-
year period.  Subjects 
removed from study 
for unacceptable 
adverse event(s) will 
be followed until 
resolution or 
stabilization of the 
adverse event.” 
For clarification 
and to adhere to 
NU template 
format. 
4.6 Removal of 
Subjects from Study 
Treatment and/or 
Study as a Whole 
Section title: “Patient 
Discontinuation” 
Section Title: 
Removal of Subjects 
from Study Treatment 
and/or Study as a 
Whole” 
To adhere to NU 
template  
List of criteria for 
discontinuing patients 
from study treatment. 
 
NU Template criteria 
for patients 
discontinuing from 
study treatment. 
 
Replaced 
description of 
removal of 
subjects with NU 
template language. 
4.7 Dose 
Delays/Dose 
Modification 
Referenced CTCAE 
Version 4.0 
Updated to reference 
CTCAE Version 4.03 
Updated to utilize 
current version of 
CTCAE (Version 
4.03) 
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Northwestern University 
 
                        
Study Number: NU12G11 
66 
 
Initial Version Date: 04/28/2013 
 
 
Amendment 8: 1/3/2019 
 
Any significant clinical 
adverse event, whether 
observed by the 
investigator, or 
observed or experienced 
by the patient, will be 
reported. Any clinically 
significant change 
from baseline in a 
laboratory parameter 
will be reported as an 
adverse event. All 
clinical and laboratory 
adverse events must be 
carefully evaluated for 
severity, duration and 
relationship to 
tivozanib. 
Any adverse event, 
whether observed by 
the investigator, or 
observed or 
experienced by the 
patient, will be 
reported. All clinical 
and laboratory adverse 
events must be 
carefully evaluated for 
severity, duration and 
relationship to 
tivozanib. 
To adhere to NU 
template language.  
All AEs (not just 
clinically 
significant) will be 
reported. 
4.7.1 Tivozanib 
Hydrochloride Dose 
Modification 
Footnote #1 directing to 
Section 5.5.5 and 6.1.4 
Footnote #1 directing 
to Appendix C 
Formatting 
N/A 
Added footnote: 
“Referring to toxicity 
that persists despite 
appropriate medical 
care.” 
For clarification 
N/A 
Added: “Tivozanib 
may be interrupted for 
up to 2 weeks. If a 
subject is able to 
resume treatment after 
an interruption of ≤ 2 
weeks, missed doses 
will not be made up 
(i.e. the cycle duration 
will remain 
unchanged). If any 
drug related toxicity 
results in interruption 
of >2 weeks, the 
subject should be 
discontinued from 
study treatment unless 
there is clear benefit.” 
For clarification 
Description of 
Tivozanib dose 
delay/modification 
Replaced original text 
with standard 
language used in 
Replaced original 
text to clarify 
instructions. 
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Northwestern University 
 
                        
Study Number: NU12G11 
67 
 
Initial Version Date: 04/28/2013 
 
 
Amendment 8: 1/3/2019 
 
previous tivozanib 
study 
4.7.2 Tivozanib 
Hydrochloride Dose 
Reduction 
The dose of tivozanib 
hydrochloride may be 
reduced to 1.0 mg/day.   
Removed redundant 
sentence on dose 
reduction. 
Repeated text from 
previous 
paragraph. 
4.7.1 Management of 
Hematologic 
Toxicity 
Explanation on dose 
modifications due to 
hematologic toxicity 
Information is 
included in Section 
4.7.1 under Tivozanib 
Hydrochloride Dose 
Modification. 
 
4.7.1 Management of 
Hypertension 
Explanation on 
treatment for 
hypertension 
This section was 
moved to Appendix C 
that contains further 
information on 
treatment for 
hypertension. 
Section was 
moved to keep 
information on 
hypertension all in 
one place – 
Appendix C 
5.2.1 Measurable 
Disease 
“…All tumor 
measurements must be 
recorded in decimal 
fractions of 
centimeters.” 
Further explanation of 
tumor measurement 
specifics as well as 
incorporating lymph 
node measurement. 
For clarification. 
5.2.2 Non-
measureable disease 
“… Leptomeningeal 
disease, ascites, 
pleural/pericardial 
effusions, lymphangitis 
cutis/pulmonitis, and 
inflammatory breast 
disease are considered 
as non-measurable.” 
“…Bone lesions, 
leptomeningeal 
disease, ascites, 
pleural/pericardial 
effusions, 
lymphangitis 
cutis/pulmonis, 
inflammatory breast 
disease, abdominal 
masses (specifically 
abdominal masses 
that cannot be 
followed by CT or 
MRI), and cystic 
lesions are all non-
measurable.” 
Expanded on non-
measurable disease 
types to have a 
more current list. 
5.2.3 Target Lesions 
Instructions for 
evaluating target lesions 
Replaced with 
identical instruction in 
a more concise 
manner 
For clarification 
5.3 Methods for 
Evaluation of 
Measurable Disease 
N/A 
Added text “Imaging-
based evaluation is 
preferred to evaluation 
by clinical 
examination when 
For clarification 
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Northwestern University 
 
                        
Study Number: NU12G11 
68 
 
Initial Version Date: 04/28/2013 
 
 
Amendment 8: 1/3/2019 
 
both methods have 
been used to assess the 
antitumor effect of a 
treatment.” 
5.3.1 Clinical 
Lesions 
N/A 
Added text “For 
superficial lesions 
measured by caliper, 
documentation by 
color photography 
including a ruler in the 
field of view is 
strongly 
recommended.” 
For clarification 
5.3.8 CA-125 
“A response according 
to CA 125 has occurred 
if there is at least a 50% 
reduction in CA 125 
levels from a 
pretreatment sample. 
The response must be 
confirmed and 
maintained for at least 
28 days.  A complete 
response has occurred if 
the CA-125 level 
decreases into the 
normal range.” 
Replaced with “See 
section 5.4.3 for 
explanation of clinical 
response.” 
Portion of the text 
is already stated in 
section 5.4.3.  
Removed to avoid 
repetition. 
7.1 Schedule of 
Assessments 
Numbers identifying 
scheduled activity 
Numbers replaced 
with Xs 
For clarification 
and to adhere to 
NU template. 
N/A 
Windows added to 
cycle activities 
For clarification, 
to avoid 
scheduling 
deviations 
History and Physical 
History and Physical 
Exam 
For clarification 
“Electrolytes, BUN, 
Glucose, Albumin, 
Creatinine, 
Ca14, Mg, PO4” 
CMP + electrolytes 
For clarification.  
Specific tests are 
footnoted (14) 
N/A 
Direct and indirect 
bilirubin 
For clarification 
Chest imaging (X ray or 
CT imaging) 
X-ray or CT imaging 
(chest/abdomen/pelvis
) 
For clarification 
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Northwestern University 
 
                        
Study Number: NU12G11 
69 
 
Initial Version Date: 04/28/2013 
 
 
Amendment 8: 1/3/2019 
 
N/A 
Echocardiogram 
(ECHO)/MUGA 
added 
Added because 
LVEF drop is a 
known side effect 
of tivozanib. 
N/A 
Added “Survival 
Status” 
For clarification 
Weekly toxicity 
assessment throughout 
the study 
Weekly toxicity 
assessment during 
cycle 1 only by clinic 
visit, phone or email. 
Weekly toxicity 
assessment not 
needed weekly 
(performed at each 
cycle visit) beyond 
cycle 1. 
N/A 
In footnote #8, 
included “absolute or 
estimated via complete 
urinalysis” as methods 
for urinalysis. 
Expand methods 
of capturing 
urinalysis.  In 
some clinics 
dipstick is not 
available. 
“If protein is 2+ or 
higher, 24-hour urine 
protein should be 
obtained and the level 
must be <1000 mg 
(<1g/24hrs) for patient 
enrollment.” 
“If protein is 3+ or 
higher, 24-hour urine 
protein should be 
obtained and the level 
must be <1000 mg 
(<1g/24hrs) for patient 
to continue on 
study.” 
Patient eligibility 
requires urine 
protein <2, once 
patient is enrolled 
in study, if protein 
is 2+, 24hr urine 
protein should be 
obtained. 
N/A 
For X-Ray/CT 
imaging “If abnormal 
at baseline, repeat 
every other cycle (or 
the equivalent 
timeframe for patient 
off treatment prior to 
disease progression) 
for the first 6 months.” 
For patient safety 
Footnote: “See the 
guidelines provided in 
Section 6.0 regarding 
treatment with tivozanib 
and proteinuria. Each 
value should be 
recorded on the D2R 
form, for the 
appropriate cycle.” 
Text removed. 
Sections 
referenced in text 
were not included 
in protocol.  
Proteinuria 
management 
should be 
performed 
according to 
section 4.7. 
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Northwestern University 
 
                        
Study Number: NU12G11 
70 
 
Initial Version Date: 04/28/2013 
 
 
Amendment 8: 1/3/2019 
 
Pretreatment 
evaluations 
Description of 
pretreatment 
evaluations 
Text was removed 
Text no longer 
required in the NU 
Template. 
Repetitive from 
schedule of 
assessment table. 
Evaluations during 
Treatment 
Description of 
evaluations during 
treatment 
Text was removed 
Text no longer 
required in the NU 
Template. 
Repetitive from 
schedule of 
assessment table. 
Evaluations post 
treatment 
Description of follow 
up activities 
Text was removed 
Text no longer 
required in the NU 
Template. 
Repetitive from 
schedule of 
assessment table. 
8. Statistical 
Methods 
N/A 
“On 10/12/16 the 
Northwestern DMC 
reviewed the first 9 
evaluable patients and 
approved the study to 
open to an additional 
21 patients.  “ 
Interim analysis 
was performed 
after the first 9 
evaluable patients. 
9. Adverse Events 
N/A 
All AE description 
was replaced with NU 
Template language 
To adhere to NU 
Template 
9.3.3.4 Reporting to 
AVEO 
Pharmacovigilance/
Drug Safety and 
NCCN 
AVEO reporting to 
“Pharmacovigilance/Dr
ug Safety 
AVEO 
Pharmaceuticals, Inc 
650 E Kendall Street, 
Cambridge, MA 02142 
Phone: 617-299-5800, 
Ext 2 
Fax: 1-800-376-8513 
E-mail: 
Aveo_gds@synowledge
.com” 
AVEO reporting to 
Parexel GPPG at 
AVEOsafety@parexel
.com or by fax 1-781-
434-5957 
Per memo 
received from 
AVEO, reporting 
is now through 
Parexel. 
10. Study 
Management 
Section title 
“Administrative 
Requirements” 
Study title “Study 
Management” 
To adhere to NU 
Template 
N/A 
All study management 
description was 
To adhere to NU 
Template 
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Northwestern University 
 
                        
Study Number: NU12G11 
71 
 
Initial Version Date: 04/28/2013 
 
 
Amendment 8: 1/3/2019 
 
replaced with NU 
template language 
11.2 Appendix B 
Table of CYP3A4 
inducers or inhibitors 
List was replaced with 
a link to the master list 
of CYP3A4 inducers 
and inhibitors.  Note 
to contact pharmacy 
with questions was 
also included. 
Like to master list 
replaced table to 
ensure a current 
list of CYP3A4 
inducers or 
inhibitors is used. 
11.3 Appendix C 
N/A 
Added descriptive 
title: “Management of 
Hypertension” 
For clarification of 
appendix contents 
N/A 
Description of 
management of 
hypertension moved 
from section 4.7.1 to 
Appendix C.  
To provide all 
information of 
management of 
hypertension in 
one place. 
Appendix E 
Medwatch Form 3500A 
Removed 
Form was 
removed.  QA has 
access to this 
form. 
Appendix H 
Pill calendar 
Removed 
Pill calendar will 
be submitted as a 
separate 
document. 
Appendix I 
Data Collection and 
Submission 
Removed. 
Data collection 
and submission is 
outlined in Section 
10 Study 
Management 
Amendment 6 – June 5, 2017 
Section(s) Affected 
Prior Version 
Amendment 6 
Changes 
Rationale 
Cover Page 
Principal Investigator: 
Mario Javier Pineda, 
MD, PhD 
Principal Investigator: 
Daniela Matei, MD 
Administrative  
IND Holder: Mario 
Javier Pineda, MD, PhD 
IND Holder: Daniela 
Matei, MD 
Administrative 
Amendment 7 – October 5, 2018 
Section(s) Affected 
Prior Version 
Amendment 7 
Changes 
Rationale 
Cover Page 
Daniela Matei, MD 
listed as Sub-
Investigator 
Removed Daniela 
Matei as Sub-
Investigator 
Dr. Matei is PI of 
study and was 
listed as a Sub-I in 
error. 
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Northwestern University 
 
                        
Study Number: NU12G11 
72 
 
Initial Version Date: 04/28/2013 
 
 
Amendment 8: 1/3/2019 
 
Margaux Kanis and 
Brandon Seagle listed 
as Sub-Investigators 
Removed Margaux 
Kanis and Brandon 
Seagle as Sub 
Investigators 
Administrative. 
No longer at 
institution 
N/a 
Emma Barber listed as 
Sub-Investigator 
Administrative 
Section 2.3 
(Exploratory 
Objectives); Section 
8 (Statistical 
Methods); Section 10 
(Correlatives/Special 
Studies) 
n/a 
Two additional 
exploratory endpoints 
were added: 
 
The first exploratory 
endpoint is a 
retrospective analysis 
of archival tissue from 
all patients who have 
enrolled to measure 
the expression of 
proteins that play a 
role in VEGF 
signaling and other 
relevant oncogenic 
pathways.  The level 
of expression will be 
correlated with the 
best response to 
treatment (CR, PR, 
SD, PD). 
 
The second 
exploratory endpoint 
is a retrospective 
analysis of genetic 
reports from all 
patients who have 
enrolled, if available. 
This analysis will be 
used to correlate 
genetic mutation 
burden with response 
to treatment. 
Exploratory 
objectives have 
been added to 
identify novel 
molecular markers 
that can 
predict response to 
Tivozanib. 
 
Additional 
statistical and 
correlative 
sections have been 
added to further 
explain analysis of 
exploratory 
endpoints. 
Section 3 (Patient 
Selection) 
Contact information for 
Dr. Mario Pineda 
Removed contact 
information for Dr. 
Pineda and replaced 
with Dr. Daniela 
Matei. 
Administrative.  
Correction of 
error. 
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Northwestern University 
 
                        
Study Number: NU12G11 
73 
 
Initial Version Date: 04/28/2013 
 
 
Amendment 8: 1/3/2019 
 
Section 4.5 
(Duration of Follow 
Up); Section 7.1 
(Schedule of 
Assessments) 
“Patients will return for 
an end of treatment visit 
within 30 days (±3 
days) of the last dose 
of study treatment.” 
“Patients will return 
for an end of treatment 
visit within ±14 days 
of the decision to 
discontinue 
treatment.” 
Timing of the End of 
Treatment visit 
has been 
corrected to 
reflect that the 
end of treatment 
visit occurs at the 
time of 
progression or 
decision to 
discontinue 
treatment 
“Subjects will be 
followed for every 3 
months for 2 years and 
then every 6 months for 
3 years after removal 
from study or until 
death, whichever occurs 
first.” 
“Subjects will be 
followed 
approximately 30 
days after 
discontinuation of 
treatment and then 
approximately every 
3 months for 2 years 
and then 
approximately every 
6 months for 3 years 
after removal from 
study or until death, 
whichever occurs 
first.” 
Clarification of timing 
of follow up. 
Section 7.1 
(Schedule of 
Assessment) 
n/a 
Addition of MR as 
imaging option in the 
table and including x-
ray in footnote #11 
Clarification to align 
the table and 
footnote 
information. 
Footnotes 1 & 2: 
procedures obtained 
prior to “initiating 
protocol therapy” 
Footnotes 1 & 2: 
procedures obtained 
prior to “study 
registration” 
Corrected to  
n/a 
Footnote # 14 added 
“Magnesium and 
Phosphorus are only 
required if clinically 
indicated” 
Added to align with 
footnote #3 that 
says only if 
clinically 
indicated. 
n/a  
Footnote #15 was 
added “Must be 
completed within 14 
days prior to of each 
cycle.  Exceptions 
include treatment 
delays, in which case 
they would be allowed 
Added so we don’t 
have to repeat 
CA-125 or EKG 
in the case of a 1-
3 week dose 
delay, as 
insurance may 
not cover repeat 
testing 
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Northwestern University 
 
                        
Study Number: NU12G11 
74 
 
Initial Version Date: 04/28/2013 
 
 
Amendment 8: 1/3/2019 
 
within 21 days prior to 
the delayed cycle.” 
Section 8 (Statistical 
Methods); Section 
9.3.1 (Routine 
Reporting); Section 
9.3.3.1 (Reporting to 
the NU 
QAM/DSMC); 
Section 11.9 
(Publication Policy) 
Data Monitoring 
Committee “DMC” 
Data and Safety 
Monitoring 
Committee “DSMC” 
Administrative. Name 
of committee has 
been updated. 
Amendment 8 – January 3, 2019 
Section(s) Affected 
Prior Version 
Amendment 8 
Changes 
Rationale 
Cover page 
Biostatistician listed as 
Borko Jovanovic 
Biostatistician listed 
as Masha 
Kocherginsky 
Administrative 
 
 
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Northwestern University 
 
                        
Study Number: NU12G11 
75 
 
Initial Version Date: 04/28/2013 
 
 
Amendment 8: 1/3/2019 
 
 
IRB #: STU00073756-CR0005 Approved by NU IRB for use on or after 12/17/2019 through 12/16/2020.