A Biomarker Study of Tivozanib in Subjects With Advanced Renal Cell Carcinoma

• Sponsor: AVEO Pharmaceuticals, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01297244
• Collaborator: (none)
• Enrollment: 105
• Locations: 25
• Arm: 1
• Duration (Months): 21
• Patients Per Site: 4.2
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

This is an open-label, single arm, multicenter study. Subjects will be stratified by histology (clear cell versus non-clear cell). Enrollment of non-clear cell subjects will be limited to ≤ 30% of the entire study population.

Condition or Disease	Intervention/Treatment	Phase
Renal Cell Carcinoma	Drug: Tivozanib	Phase 2

Detailed Description

This is a Phase 2, open-label, single arm, multi-center, study of orally administered tivozanib to approximately 100 subjects with advanced renal cell carcinoma (RCC). This study is designed to evaluate biomarkers in blood and archived tissue samples, and their correlation with clinical activity and/or treatment-related toxicity in subjects with advanced RCC, and estimate the percentage of tivozanib-treated subjects who are progression-free at 6 months, overall response rate (ORR), progression free survival (PFS), safety and tolerability, and pharmacokinetics (PK). Subjects will be stratified by histology (clear cell vs. non-clear cell). Enrollment of non-clear cell subjects will be limited to ≤ 30% of the entire study population.

Study enrollment is anticipated to complete in approximately 9 months. Treatment duration is estimated to last approximately 6 months from the subject's first dose of tivozanib with a follow-up period of 30 days. After 6 months, treatment with tivozanib may continue by participation in a rollover protocol (AV-951-09-901). Maximum duration of subject participation in this Phase 2 study is approximately 8 months.

Study Design

• Study Type: Interventional
• Actual Enrollment: 105 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 2 and Biomarker Study of Tivozanib in Subjects With Advanced Renal Cell Carcinoma
• Study Start Date: Jan 1, 2011
• Actual Primary Completion Date: Oct 1, 2012
• Actual Study Completion Date: Oct 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Tivozanib Subjects will receive 1.5 mg tivozanib once daily beginning on Day 1 for 3 weeks followed by 1 week off treatment. One cycle will be defined as 4 weeks of treatment. Cycles will be repeated every 4 weeks.	Drug: Tivozanib; Subjects will receive 1.5 mg tivozanib once daily beginning on Day 1 for 3 weeks followed by 1 week off treatment. One cycle will be defined as 4 weeks of treatment. Cycles will be repeated every 4 weeks.

Outcome Measures

Primary Outcome Measures

1. Biomarkers in Blood and Archived Tissue Samples, and Their Correlation With Clinical Activity in Subjects With Advanced Renal Cell Cancer Treated With Tivozanib. [Cycle 1 day 1, cycle 1 day 15 and cycle 2 day 1.]

   To Evaluate CD68, HIF (hypoxia induced factor) 1/HIF2, VEGF A, VEGF-B, VEGF-C, VEGF-D, HGF (hepatocyte growth factor), CAIX, and PLGF (placental growth factor) levels and a biomarker signature based on transcriptional profiles.

2. Biomarkers in Blood and Archived Tissue Samples, and Their Correlation With Treatment-related Toxicity in Subjects With Advanced Renal Cell Cancer Treated With Tivozanib. [Cycle 1 day 1, cycle 1 day 15 and cycle 2 day 1.]

   To Evaluate biomarkers like VEGF-A, VEGF-B, VEGF-C, VEGF-D, HGF, and PLGF levels, protein expression and metabolite patterns.

3. Number of Tivozanib-treated Subjects Who Are Progression-free at 6 Months [Throughout the treatment period (approximately 6 months from the subject's first dose of tivozanib).]

   Subjects were considered to be progression-free at 6 months if they did not have disease progression or death by Day 182 and if they had an evaluation of confirmed PR, unconfirmed PR, or SD on or after Day 144.

Secondary Outcome Measures

1. Number of Subjects With Objective Response Rate (ORR) [Throughout the treatment period (approximately 6 months from the subject's first dose of tivozanib).]

   Objective response rate (ORR) is defined as the proportion of evaluable subjects who had a best overall response of complete response (CR) or partial response (PR). Based on RECIST v1.1 for target lesions, CR is the disappearance of all target lesions, reduction in short axis of any pathological lymph nodes (whether target or non-target) to < 10 mm and PR is at least a 30% decrease from baseline in the sum of diameters of target lesions.

2. Kaplan-Meier Estimate of Progression-free Survival (PFS) [Throughout the treatment period (approximately 6 months from the subject's first dose of tivozanib).]

   PFS is defined as the duration in days from the date of first dose of study drug to the date of first documentation of Progressive Disease (PD) or death (whichever came first), censored at the last tumor assessment documenting the absence of PD prior to the start of further anti-cancer therapy. Based on RECIST v1.1, progressive Disease (PD) is defined as an increase of at least 20%, and an absolute increase of at least 5 mm, in the sum of diameters of target lesions, taking as reference the smallest sum on study.

3. Number of Subjects With Adverse Events [Throughout the treatment period (approximately 6 months from the subject's first dose of tivozanib) and 30 day follow-up period.]

   Subjects were monitored throughout the treatment and 30 day follow-up period for occurrence of adverse events as well as for changes in clinical status, vital signs, and laboratory data. Safety parameters to be measured/assessed include eligibility assessment, medical history, performance status evaluation, vital signs, physical examination, subjective reports, hematology, serum chemistries, thyroid function tests, coagulation parameters, urinalysis, pregnancy test, and ECG.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. ≥ 18 year old males or females

2. Subjects with unresectable locally recurrent or metastatic renal cell carcinoma (RCC)

3. Histologically or cytologically confirmed clear cell renal cell carcinoma (≥ 50% clear cell) or non-clear cell RCC (all histologies)

4. Subjects must have undergone prior nephrectomy (complete or partial) for excision of the primary tumor.

5. Measurable disease per RECIST criteria Version 1.1 (see Appendix A)

6. Treatment naïve subjects or subjects who have received no more than one prior systemic treatment (immunotherapy, including interferon-alfa or interleukin-2 based therapy, chemotherapy, hormonal therapy or an investigational agent) for metastatic RCC.

7. Eastern Cooperative Oncology Group performance status of 0 or 1, and life expectancy ≥ 3 months

8. If female and of childbearing potential, documentation of negative pregnancy test prior to enrollment

9. Willingness to provide archival paraffin embedded tumor tissue, if available.

10. Ability to give written informed consent and comply with protocol requirements

Exclusion Criteria:

1. Any prior vascular endothelial growth factor (VEGF)-directed therapy including VEGF antibody (eg, bevacizumab), VEGF receptor tyrosine kinase inhibitor (eg, sunitinib, sorafenib, axitinib, pazopanib, etc.), VEGF trap (eg, aflibercept), or any other agent or investigational agent targeting the VEGF pathway.

2. Any prior therapy with an agent targeting the mechanistic target of rapamycin pathway (eg, temsirolimus, everolimus, etc)

3. Primary central nervous system (CNS) malignancies or CNS metastases; subjects with previously treated brain metastasis will be allowed if the brain metastasis have been stable without steroid treatment for at least 3 months following prior treatment (radiotherapy or surgery).

4. Any of the following hematologic abnormalities:

• Hemoglobin < 9.0 g/dL

• Absolute neutrophil count (ANC) < 1500 per mm3

• Platelet count < 100,000 per mm3

• International Normalized Ratio >1.5 or partial thromboplastin time >1.5 × upper limit of normal (ULN)

1. Any of the following serum chemistry abnormalities:

• Total bilirubin > 1.5 × ULN (or > 2.5 × ULN for subjects with Gilbert's syndrome)

• Aspartate aminotransferase or alanine aminotransferase > 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

• Proteinuria > 3+ by urinalysis or urine dipstick

1. Significant cardiovascular disease, including:

• Active clinically symptomatic left ventricular failure.

• Uncontrolled hypertension: Systolic blood pressure > 140 mmHg or diastolic blood pressure > 90 mmHg on 2 or more antihypertensive medications, documented on 2 consecutive measurements taken at least 24 hours apart.

• Myocardial infarction, severe angina, or unstable angina within 6 months prior to administration of first dose of study drug.

• History of serious ventricular arrhythmia (ie, ventricular tachycardia or ventricular fibrillation)

• Cardiac arrhythmias requiring anti-arrhythmic medications (except for atrial fibrillation that is well controlled with anti-arrhythmic medication)

• Coronary or peripheral artery bypass graft within 6 months of screening

1. Non-healing wound, bone fracture, or skin ulcer.

2. 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

3. Serious/active infection or infection requiring parenteral antibiotics.

4. Inadequate recovery from any prior surgical procedure or major surgical procedure within 4 weeks prior to administration of first dose of study drug.

5. 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 CTCAE Version 3.0)

1. 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 3.0)

• Hemoptysis or other pulmonary bleeding Grade 2 (per CTCAE Version 3.0)

1. Currently active second primary malignancy, including hematologic malignancies (leukemia, lymphoma, multiple myeloma, etc.), other than non-melanoma skin cancers, non-metastatic prostate cancer, in situ cervical cancer, and ductal or lobular carcinoma in situ of the breast. Subjects are not considered to have a currently active malignancy if they have completed anti-cancer therapy and have been disease free for >2 years.

2. Pregnant or lactating females.

3. History of genetic or acquired immune suppression disease such as HIV; subjects on immune suppressive therapy for organ transplant.

4. Life-threatening illness or organ system dysfunction compromising safety evaluation.

5. Requirement for hemodialysis or peritoneal dialysis.

6. Inability to swallow pills, malabsorption syndrome or gastrointestinal disease that severely affects the absorption of tivozanib, major resection of the stomach or small bowel, or gastric bypass procedure.

7. Psychiatric disorder or altered mental status precluding informed consent or protocol-related testing.

8. Sexually active pre-menopausal female subjects (and female partners of male subjects) must use adequate contraceptive measures, while on study and for 30 days after the last dose of study drug. All fertile male and female subjects must agree to use a highly effective method of contraception (including their partner). Effective birth control includes:

• intrauterine device plus one barrier method or 2 barrier methods. Effective barrier methods are male or female condoms, diaphragms, and spermicides (creams or gels that contain a chemical to kill sperm). (Note: Oral,implantable, or injectable contraceptives

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Southern Cancer Center	Mobile	Alabama	United States
2	Providence Health and Services	Burbank	California	United States
3	David Geffen School of Medicine at UCLA	Los Angeles	California	United States
4	Rocky Mountain Cancer Center	Denver	Colorado	United States
5	St. Francis Cancer Research Foundation	Beech Grove	Indiana	United States
6	Cancer Center of Kansas	Wichita	Kansas	United States
7	Medical Oncology, LLC	Baton Rouge	Louisiana	United States
8	Dana Farber Cancer Institute	Boston	Massachusetts	United States
9	Cancer & Hematology Centers of Western Michigan	Grand Rapids	Michigan	United States
10	North Mississippi Hematology & Oncology Associates, Ltd.	Tupelo	Mississippi	United States
11	Comprehensive Cancer Centers of Nevada & US Oncology Research	Las Vegas	Nevada	United States
12	Mary Hitchcock Memorial Hospital, NH	Lebanon	New Hampshire	United States
13	University of North Carolina, Lineberger Comprehensive Cancer Center	Chapel Hill	North Carolina	United States
14	Ohio State University	Columbus	Ohio	United States
15	Fox Chase Cancer Center	Philadelphia	Pennsylvania	United States
16	The Jones Clinic	Germantown	Tennessee	United States
17	The West Clinic	Memphis	Tennessee	United States
18	Texas Oncology-Austin North	Austin	Texas	United States
19	Coastal Bend Cancer Center	Corpus Christi	Texas	United States	78404
20	Texas Oncology-Baylor, Charles A. Sammons Cancer Center	Dallas	Texas	United States
21	BC Cancer Agency Vancouver Centre	Vancouver	British Columbia	Canada
22	Juravinski Cancer Center	Hamilton	Ontario	Canada
23	Princess Margaret Hospital	Toronto	Ontario	Canada
24	Sunnybrook Odette Cancer Center, Toronto	Toronto	Ontario	Canada
25	Montreal General Hospital	Montreal	Quebec	Canada

Sponsors and Collaborators

• AVEO Pharmaceuticals, Inc.

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: AVEO Pharmaceuticals, Inc.
• ClinicalTrials.gov Identifier: NCT01297244
• Other Study ID Numbers: AV-951-10-202
• First Posted: Feb 16, 2011
• Last Update Posted: Oct 27, 2020
• Last Verified: Oct 1, 2020

• Keywords provided by AVEO Pharmaceuticals, Inc.: AV-951; Tivozanib; RCC; Biomarkers; Advanced Renal Cell Carcinoma
• Additional relevant MeSH terms: Carcinoma; Carcinoma, Renal Cell

Study Results

Participant Flow

Recruitment Details	Subjects who met all the inclusion and none of the exclusion criteria were enrolled in 2 sites in the United States and Canada.
Pre-assignment Detail	All screening assessments were performed within 21 days prior to the first dose of study drug. All subjects underwent inclusion exclusion criteria assessment and all eligible participants signed the informed consent before undergoing any study-related procedures.

Arm/Group Title	Clear Cell RCC	Non-Clear Cell RCC
Arm/Group Description	Subjects received 1.5 mg tivozanib orally once daily beginning on Cycle 1 Day 1 for 3 weeks followed by 1 week off treatment. One cycle is defined as 4 weeks of treatment. Cycles are repeated every 4 weeks.	Subjects received 1.5 mg tivozanib orally once daily beginning on Cycle 1 Day 1 for 3 weeks followed by 1 week off treatment. One cycle is defined as 4 weeks of treatment. Cycles are repeated every 4 weeks.
Period Title: Overall Study
STARTED	90	15
COMPLETED	55	9
NOT COMPLETED	35	6

Baseline Characteristics

Arm/Group Title	Clear Cell RCC	Non-Clear Cell RCC	Total
Arm/Group Description	Subjects received 1.5 mg tivozanib orally once daily beginning on Cycle 1 Day 1 for 3 weeks followed by 1 week off treatment. One cycle is defined as 4 weeks of treatment. Cycles are repeated every 4 weeks.	Subjects received 1.5 mg tivozanib orally once daily beginning on Cycle 1 Day 1 for 3 weeks followed by 1 week off treatment. One cycle is defined as 4 weeks of treatment. Cycles are repeated every 4 weeks.	Total of all reporting groups
Overall Participants	90	15	105
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	60 (9.99)	64.7 (9.26)	60.7 (9.98)
Sex: Female, Male (Count of Participants)
Female	23 25.6%	1 6.7%	24 22.9%
Male	67 74.4%	14 93.3%	81 77.1%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	10 11.1%	0 0%	10 9.5%
Not Hispanic or Latino	78 86.7%	15 100%	93 88.6%
Unknown or Not Reported	2 2.2%	0 0%	2 1.9%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	2 2.2%	1 6.7%	3 2.9%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	5 5.6%	1 6.7%	6 5.7%
White	80 88.9%	13 86.7%	93 88.6%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	3 3.3%	0 0%	3 2.9%

Outcome Measures

1. Primary Outcome

Title	Biomarkers in Blood and Archived Tissue Samples, and Their Correlation With Clinical Activity in Subjects With Advanced Renal Cell Cancer Treated With Tivozanib.
Description	To Evaluate CD68, HIF (hypoxia induced factor) 1/HIF2, VEGF A, VEGF-B, VEGF-C, VEGF-D, HGF (hepatocyte growth factor), CAIX, and PLGF (placental growth factor) levels and a biomarker signature based on transcriptional profiles.
Time Frame	Cycle 1 day 1, cycle 1 day 15 and cycle 2 day 1.

Outcome Measure Data

Analysis Population Description

The primary efficacy analyses of correlations between biomarkers in blood and archived tissue and PFS and objective response were not completed due to voluntary study discontinuation. Therefore, data was not collected for this outcome measure.

Arm/Group Title	Tivozanib
Arm/Group Description	Subjects will receive 1.5 mg tivozanib once daily beginning on Day 1 for 3 weeks followed by 1 week off treatment. One cycle will be defined as 4 weeks of treatment. Cycles will be repeated every 4 weeks. Tivozanib: Subjects will receive 1.5 mg tivozanib once daily beginning on Day 1 for 3 weeks followed by 1 week off treatment. One cycle will be defined as 4 weeks of treatment. Cycles will be repeated every 4 weeks.
Measure Participants	0

2. Primary Outcome

Title	Biomarkers in Blood and Archived Tissue Samples, and Their Correlation With Treatment-related Toxicity in Subjects With Advanced Renal Cell Cancer Treated With Tivozanib.
Description	To Evaluate biomarkers like VEGF-A, VEGF-B, VEGF-C, VEGF-D, HGF, and PLGF levels, protein expression and metabolite patterns.
Time Frame	Cycle 1 day 1, cycle 1 day 15 and cycle 2 day 1.

Outcome Measure Data

Analysis Population Description

The primary efficacy analyses of correlations between biomarkers in blood and archived tissue and PFS and objective response were not completed due to voluntary study discontinuation. Therefore, data was not collected for this outcome measure.

Arm/Group Title	Tivozanib
Arm/Group Description	Subjects will receive 1.5 mg tivozanib once daily beginning on Day 1 for 3 weeks followed by 1 week off treatment. One cycle will be defined as 4 weeks of treatment. Cycles will be repeated every 4 weeks. Tivozanib: Subjects will receive 1.5 mg tivozanib once daily beginning on Day 1 for 3 weeks followed by 1 week off treatment. One cycle will be defined as 4 weeks of treatment. Cycles will be repeated every 4 weeks.
Measure Participants	0

3. Primary Outcome

Title	Number of Tivozanib-treated Subjects Who Are Progression-free at 6 Months
Description	Subjects were considered to be progression-free at 6 months if they did not have disease progression or death by Day 182 and if they had an evaluation of confirmed PR, unconfirmed PR, or SD on or after Day 144.
Time Frame	Throughout the treatment period (approximately 6 months from the subject's first dose of tivozanib).

Outcome Measure Data

Analysis Population Description

Intent-to-treat population (ITT): All enrolled subjects who receive at least 1 dose of tivozanib.

Arm/Group Title	Clear Cell RCC	Non-Clear Cell RCC
Arm/Group Description	Subjects received 1.5 mg tivozanib orally once daily beginning on Cycle 1 Day 1 for 3 weeks followed by 1 week off treatment. One cycle is defined as 4 weeks of treatment. Cycles are repeated every 4 weeks.	Subjects received 1.5 mg tivozanib orally once daily beginning on Cycle 1 Day 1 for 3 weeks followed by 1 week off treatment. One cycle is defined as 4 weeks of treatment. Cycles are repeated every 4 weeks.
Measure Participants	90	15
Count of Participants [Participants]	49 54.4%	7 46.7%

4. Secondary Outcome

Title	Number of Subjects With Objective Response Rate (ORR)
Description	Objective response rate (ORR) is defined as the proportion of evaluable subjects who had a best overall response of complete response (CR) or partial response (PR). Based on RECIST v1.1 for target lesions, CR is the disappearance of all target lesions, reduction in short axis of any pathological lymph nodes (whether target or non-target) to < 10 mm and PR is at least a 30% decrease from baseline in the sum of diameters of target lesions.
Time Frame	Throughout the treatment period (approximately 6 months from the subject's first dose of tivozanib).

Outcome Measure Data

Analysis Population Description

Intent-to-treat population (ITT): All enrolled subjects who receive at least 1 dose of tivozanib.

Arm/Group Title	Clear Cell RCC	Non-Clear Cell RCC
Arm/Group Description	Subjects received 1.5 mg tivozanib orally once daily beginning on Cycle 1 Day 1 for 3 weeks followed by 1 week off treatment. One cycle is defined as 4 weeks of treatment. Cycles are repeated every 4 weeks.	Subjects received 1.5 mg tivozanib orally once daily beginning on Cycle 1 Day 1 for 3 weeks followed by 1 week off treatment. One cycle is defined as 4 weeks of treatment. Cycles are repeated every 4 weeks.
Measure Participants	90	15
Count of Participants [Participants]	24 26.7%	2 13.3%

5. Secondary Outcome

Title	Kaplan-Meier Estimate of Progression-free Survival (PFS)
Description	PFS is defined as the duration in days from the date of first dose of study drug to the date of first documentation of Progressive Disease (PD) or death (whichever came first), censored at the last tumor assessment documenting the absence of PD prior to the start of further anti-cancer therapy. Based on RECIST v1.1, progressive Disease (PD) is defined as an increase of at least 20%, and an absolute increase of at least 5 mm, in the sum of diameters of target lesions, taking as reference the smallest sum on study.
Time Frame	Throughout the treatment period (approximately 6 months from the subject's first dose of tivozanib).

Outcome Measure Data

Analysis Population Description

Intent-to-treat population (ITT): All enrolled subjects who receive at least 1 dose of tivozanib.

Arm/Group Title	Clear Cell RCC	Non-Clear Cell RCC
Arm/Group Description	Subjects received 1.5 mg tivozanib orally once daily beginning on Cycle 1 Day 1 for 3 weeks followed by 1 week off treatment. One cycle is defined as 4 weeks of treatment. Cycles are repeated every 4 weeks.	Subjects received 1.5 mg tivozanib orally once daily beginning on Cycle 1 Day 1 for 3 weeks followed by 1 week off treatment. One cycle is defined as 4 weeks of treatment. Cycles are repeated every 4 weeks.
Measure Participants	90	15
Median (95% Confidence Interval) [Weeks]	25.0	23.6

6. Secondary Outcome

Title	Number of Subjects With Adverse Events
Description	Subjects were monitored throughout the treatment and 30 day follow-up period for occurrence of adverse events as well as for changes in clinical status, vital signs, and laboratory data. Safety parameters to be measured/assessed include eligibility assessment, medical history, performance status evaluation, vital signs, physical examination, subjective reports, hematology, serum chemistries, thyroid function tests, coagulation parameters, urinalysis, pregnancy test, and ECG.
Time Frame	Throughout the treatment period (approximately 6 months from the subject's first dose of tivozanib) and 30 day follow-up period.

Outcome Measure Data

Analysis Population Description

ITT: All enrolled subjects who receive at least 1 dose of tivozanib. Although an additional subject had a serious adverse event of pneumonia in the Non-Clear Cell RCC that was documented as cause of death, this event is not included under "TEAE resulting in death" as it was not treatment emergent (onset was 30 days after the last dose).

Arm/Group Title	Clear Cell RCC	Non-Clear Cell RCC
Arm/Group Description	Subjects received 1.5 mg tivozanib orally once daily beginning on Cycle 1 Day 1 for 3 weeks followed by 1 week off treatment. One cycle is defined as 4 weeks of treatment. Cycles are repeated every 4 weeks.	Subjects received 1.5 mg tivozanib orally once daily beginning on Cycle 1 Day 1 for 3 weeks followed by 1 week off treatment. One cycle is defined as 4 weeks of treatment. Cycles are repeated every 4 weeks.
Measure Participants	90	15
Any TEAE	90 100%	15 100%
Study drug-related TEAE	87 96.7%	15 100%
Any TEAE of Grade 3 or higher	67 74.4%	11 73.3%
Study drug-related TEAE of Grade 3 or higher	61 67.8%	10 66.7%
TEAE resulting in death	1 1.1%	0 0%
Study drug-related TEAE resulting in death	0 0%	0 0%
Serious TEAE	16 17.8%	2 13.3%
Study drug-related serious TEAE	7 7.8%	0 0%
TEAE-discontinuation of study drug	10 11.1%	1 6.7%
Study drug-related TEAE-discontinuation-study drug	8 8.9%	1 6.7%
TEAE-reduction of study drug dose	10 11.1%	1 6.7%
Study drug-related TEAE-reduction of study drug	9 10%	1 6.7%
TEAE-interruption of study drug dosing	19 21.1%	4 26.7%
Study drug-related TEAE-interruption of study drug	14 15.6%	3 20%

Adverse Events

Time Frame	Throughout the treatment period (approximately 6 months from the subject's first dose of tivozanib) and 30 day follow-up period.
Adverse Event Reporting Description	Serious treatment-emergent adverse events and treatment emergent adverse events in Intent-To-Treat Population is reported.
Arm/Group Title	Clear Cell RCC		Non-Clear Cell RCC
Arm/Group Description	Subjects received 1.5 mg tivozanib orally once daily beginning on Cycle 1 Day 1 for 3 weeks followed by 1 week off treatment. One cycle is defined as 4 weeks of treatment. Cycles are repeated every 4 weeks.		Subjects received 1.5 mg tivozanib orally once daily beginning on Cycle 1 Day 1 for 3 weeks followed by 1 week off treatment. One cycle is defined as 4 weeks of treatment. Cycles are repeated every 4 weeks.
All Cause Mortality
	Clear Cell RCC		Non-Clear Cell RCC
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Clear Cell RCC		Non-Clear Cell RCC
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	16/90 (17.8%)		2/15 (13.3%)
Cardiac disorders
Acute coronary syndrome	1/90 (1.1%)		0/15 (0%)
Acute myocardial infarction	1/90 (1.1%)		0/15 (0%)
Cardiac arrest	1/90 (1.1%)		0/15 (0%)
Endocrine disorders
Adrenal hemorrhage	1/90 (1.1%)		0/15 (0%)
Gastrointestinal disorders
Pancreatitis	2/90 (2.2%)		0/15 (0%)
Constipation	1/90 (1.1%)		0/15 (0%)
General disorders
Asthenia	2/90 (2.2%)		1/15 (6.7%)
Non-cardiac chest pain	1/90 (1.1%)		0/15 (0%)
Infections and infestations
Herpes zoster	1/90 (1.1%)		0/15 (0%)
Cellulitis	1/90 (1.1%)		0/15 (0%)
Urosepsis	1/90 (1.1%)		0/15 (0%)
Injury, poisoning and procedural complications
Gastroenteritis radiation	1/90 (1.1%)		0/15 (0%)
Musculoskeletal and connective tissue disorders
Back pain	1/90 (1.1%)		0/15 (0%)
Flank pain	1/90 (1.1%)		0/15 (0%)
Nervous system disorders
Transient ischemic attack	1/90 (1.1%)		0/15 (0%)
Renal and urinary disorders
Renal failure acute	1/90 (1.1%)		0/15 (0%)
Respiratory, thoracic and mediastinal disorders
Dyspnea	1/90 (1.1%)		1/15 (6.7%)
Other (Not Including Serious) Adverse Events
	Clear Cell RCC		Non-Clear Cell RCC
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	90/90 (100%)		15/15 (100%)
Endocrine disorders
Hypothyroidism	17/90 (18.9%)		6/15 (40%)
Eye disorders
Vision blurred	9/90 (10%)		0/15 (0%)
Gastrointestinal disorders
Abdominal pain	12/90 (13.3%)		6/15 (40%)
Abdominal pain upper	9/90 (10%)		1/15 (6.7%)
Constipation	19/90 (21.1%)		1/15 (6.7%)
Diarrhoea	44/90 (48.9%)		8/15 (53.3%)
Dry mouth	5/90 (5.6%)		3/15 (20%)
Dyspepsia	20/90 (22.2%)		4/15 (26.7%)
Flatulence	8/90 (8.9%)		1/15 (6.7%)
Gastrooesophageal reflux disease	8/90 (8.9%)		2/15 (13.3%)
Nausea	40/90 (44.4%)		12/15 (80%)
Pancreatitis	6/90 (6.7%)		0/15 (0%)
Stomatitis	26/90 (28.9%)		5/15 (33.3%)
Vomiting	18/90 (20%)		5/15 (33.3%)
General disorders
Asthenia	5/90 (5.6%)		3/15 (20%)
Fatigue	53/90 (58.9%)		8/15 (53.3%)
Oedema peripheral	8/90 (8.9%)		1/15 (6.7%)
Pain	6/90 (6.7%)		1/15 (6.7%)
Infections and infestations
Nasopharyngitis	6/90 (6.7%)		0/15 (0%)
Upper respiratory tract infection	4/90 (4.4%)		2/15 (13.3%)
Investigations
Amylase increased	8/90 (8.9%)		0/15 (0%)
Blood creatinine increased	5/90 (5.6%)		1/15 (6.7%)
Lipase increased	13/90 (14.4%)		5/15 (33.3%)
Weight decreased	10/90 (11.1%)		4/15 (26.7%)
Metabolism and nutrition disorders
Decreased appetite	30/90 (33.3%)		4/15 (26.7%)
Dehydration	6/90 (6.7%)		1/15 (6.7%)
Hyperkalaemia	5/90 (5.6%)		3/15 (20%)
Musculoskeletal and connective tissue disorders
Arthralgia	13/90 (14.4%)		5/15 (33.3%)
Back pain	25/90 (27.8%)		1/15 (6.7%)
Flank pain	8/90 (8.9%)		0/15 (0%)
Muscle spasms	7/90 (7.8%)		1/15 (6.7%)
Musculoskeletal pain	6/90 (6.7%)		2/15 (13.3%)
Myalgia	5/90 (5.6%)		2/15 (13.3%)
Pain in extremity	10/90 (11.1%)		2/15 (13.3%)
Nervous system disorders
Dizziness	16/90 (17.8%)		2/15 (13.3%)
Dysgeusia	11/90 (12.2%)		2/15 (13.3%)
Headache	25/90 (27.8%)		4/15 (26.7%)
Psychiatric disorders
Anxiety	10/90 (11.1%)		0/15 (0%)
Depression	6/90 (6.7%)		1/15 (6.7%)
Insomnia	10/90 (11.1%)		0/15 (0%)
Renal and urinary disorders
Proteinuria	11/90 (12.2%)		4/15 (26.7%)
Respiratory, thoracic and mediastinal disorders
Cough	11/90 (12.2%)		4/15 (26.7%)
Dysphonia	42/90 (46.7%)		9/15 (60%)
Dyspnoea	20/90 (22.2%)		3/15 (20%)
Epistaxis	5/90 (5.6%)		3/15 (20%)
Oropharyngeal pain	5/90 (5.6%)		1/15 (6.7%)
Rhinorrhoea	8/90 (8.9%)		2/15 (13.3%)
Skin and subcutaneous tissue disorders
Dermatitis acneiform	5/90 (5.6%)		1/15 (6.7%)
Dry skin	8/90 (8.9%)		2/15 (13.3%)
Palmar-plantar erythrodysaesthesia syndrome	19/90 (21.1%)		1/15 (6.7%)
Pruritus	5/90 (5.6%)		1/15 (6.7%)
Rash	6/90 (6.7%)		3/15 (20%)
Vascular disorders
Hypertension	58/90 (64.4%)		9/15 (60%)

Limitations/Caveats

The primary efficacy analyses of correlations between biomarkers in blood and archived tissue and PFS and objective response were not completed due to voluntary study discontinuation.

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Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.