A Phase 2 and Biomarker Study of Tivozanib in Subjects With Advanced Renal Cell Carcinoma

Inclusion Criteria:

1. ≥ 18 year old males or females

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

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. ECOG 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 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 mTOR pathway (eg, temsirolimus,
everolimus, etc)

3. Primary 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

- INR >1.5 or PTT >1.5 × ULN

5. Any of the following serum chemistry abnormalities:

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

- AST or ALT > 2.5 × ULN (or > 5 × ULN for subjects with liver metastasis)

- Alkaline phosphatase > 2.5 × ULN (or > 5 × ULN for subjects with liver or
bone metastasis)

- Creatinine > 2.0 × ULN

- Proteinuria > 3+ by urinalysis or urine dipstick

6. 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

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

8. Active peptic ulcer disease, inflammatory bowel disease, ulcerative colitis, or other
gastrointestinal condition with increased risk of perforation; history of abdominal
fistula, gastrointestinal perforation, or intra-abdominal abscess within 4 weeks
prior to administration of first dose of study drug

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

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

11. Significant thromboembolic or vascular disorders within 6 months prior to
administration of first dose of study drug, including but not limited to:

- Deep vein thrombosis

- Pulmonary embolism

- Cerebrovascular accident (CVA) or transient ischemic attack (TIA)

- Peripheral arterial ischemia > Grade 2 (per CTCAE Version 3.0)

12. Significant bleeding disorders within 6 months prior to administration of first dose
of study drug, including but not limited to.

- Hematemesis, hematochezia, melena or other gastrointestinal bleeding Grade 2
(per CTCAE Version 3.0)

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

13. 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.

14. Pregnant or lactating females.

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

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

17. Requirement for hemodialysis or peritoneal dialysis.

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

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

20. 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:

- IUD 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