An Extension Treatment Protocol for Subjects Who Have Participated in a Study of Tivozanib Versus Sorafenib in Kidney Carcinoma (Protocol AV-951-09-301).

An Extension Treatment Protocol for Subjects Who Have Participated in a Phase 3 Study of Tivozanib vs. Sorafenib in Renal Cell Carcinoma (Protocol AV-951-09-301).

Open-label, multi-center extension treatment protocol to allow access to tivozanib and sorafenib for subjects who have participated on the AV-951-09-301 protocol. Eligible subjects who were randomized to receive sorafenib on AV-951-09-301 and had documented progression of disease will receive a tivozanib dose of 1.5 mg/day. Eligible subjects who were randomized to tivozanib or sorafenib in AV-951-09-301, and displayed clinical benefit and acceptable tolerability to treatment, will continue to receive tivozanib or sorafenib at the same dose and schedule as in AV-951-09-301.

This is an extension treatment protocol to allow access to tivozanib or sorafenib for subjects enrolled on AV-951-09-301(parent protocol). Subjects who failed sorafenib on the parent protocol will be offered tivozanib. Subjects who were randomized to tivozanib, and demonstrated clinical benefit and acceptable tolerability will be offered long-term access to tivozanib. Subjects who were randomized to sorafenib, and demonstrated clinical benefit and acceptable tolerability will be offered long-term access to sorafenib. Subjects who continue receiving sorafenib on this protocol and progress will be allowed to cross-over to tivozanib.

Inclusion Criteria:

1. The subject must have participated on Protocol AV-951-09-301, and must meet either of the following bulleted criteria:

   • Demonstrated disease progression per RECIST during treatment with sorafenib, OR
   • Demonstrated clinical benefit [complete response (CR), partial response (PR), or stable disease (SD) per RECIST] and acceptable tolerability after treatment with tivozanib or sorafenib on protocol AV-951-09-301.

2. Eastern Cooperative Oncology Group performance status ≤ 2 and life expectancy ≥ 3 months.

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

4. Ability to give written informed consent

Exclusion Criteria:

1. Newly identified central nervous system (CNS) malignancies or documented progression of CNS metastases; subjects will be allowed only if the CNS metastases have been adequately treated with radiotherapy or surgery. For subjects receiving steroid therapy for allowed steroid maintenance therapy.

2. Duration since last dose on Protocol AV-951-09-301:

   1. For subjects continuing tivozanib or sorafenib (subjects who demonstrated clinical benefit and acceptable tolerability during treatment with tivozanib or sorafenib on protocol AV-951-09-301): more than 2 weeks since last dose of tivozanib or sorafenib.
   2. For subjects initiating tivozanib (ie demonstrated disease progression during treatment with sorafenib): more than 4 weeks since last dose of sorafenib. Subjects demonstrating disease progression due to CNS metastasis will be allowed up to 8 weeks since last dose of sorafenib in order to complete treatment for CNS metastasis.

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

4. Any of the following hematologic abnormalities:

   • Hemoglobin < 9.0 g/dL
   • Absolute neutrophil count < 1500 per mm3
   • Platelet count < 75,000 per mm3
   • Prothrombin time or Partial thromboplastin time >1.5 × upper limit of normal (ULN)

5. 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

6. If female, pregnant or lactating.

7. Sexually active pre-menopausal female subjects (and female partners of male subjects) must use adequate contraceptive measures, while on study and for at least 50 days after the last dose of study drug. Sexually active male subjects must use adequate contraceptive measures, while on study and for at least 90 days after the last dose of study drug. All fertile male and female subjects,and their partners,must agree to use a highly effective method of contraception. Effective birth control includes (a) Intrauterine device plus one barrier method; or (b) 2 barrier methods. Effective barrier methods are male or female condoms, diaphragms, and spermicides (creams or gels that contain a chemical to kill sperm). (Note: Oral, implantable, or injectable contraceptives may be affected by cytochrome P450 interactions, and are not considered effective for this study).

8. Uncontrolled hypertension: systolic blood pressure > 150 mmHg or diastolic blood pressure >100 mmHg on 2 or more antihypertensive medications, documented on 2 consecutive measurements taken at least 24 hours apart.

9. Unhealed wounds (including active peptic ulcers).

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

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

12. Psychiatric disorder, altered mental status precluding informed consent or necessary testing.

13. Inability to comply with protocol requirements.

14. Treatment with another anti-cancer therapy or participation in another interventional protocol (excluding AV-951-09-301).