• Removed objective “to determine overall survival (OS) of subjects treated on tivozanib protocols.” • Timings of sample collection (hematology, serum chemistries, urinalysis) updated to "on the first day of Cycle 1 and on the first day of odd numbered cycles thereafter (Cycle 3, Cycle 5, etc.)." • Clarified that laboratory values were be collected on the appropriate CRF page and that clinically significant changes (CS) reported as AEs were to be noted as CS on the appropriate CRF page. • A new section "7.1.10 Concomitant Medications" was added to clarify the collection of concomitant medications.

• Description of Day 1 assessments was updated in line with Table 1. • Exclusion criterion #4 was changed to systolic blood pressure > 140 mmHg or diastolic blood pressure > 90 mmHg • A new criterion was added "newly identified 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 please refer to protocol for allowed steroid maintenance therapy" • Timing of safety monitoring was specified on Day 1 of every cycle. Tivozanib (plus combination agent, if applicable) was added to the data to be monitored. • Added Study Drug Diary, column for Unscheduled Visits, and Disease Assessment footnotes #4 and #5 under Schedule of Events section. • Reference to minimum allowed doses was deleted under rationale for the dose section. • Clarified that 4 weeks following treatment is measured from 30 days after the last dose of tivozanib. • The timing of hematology, chemistries, and urinalysis assessments was updated to “on Day 1 of Cycle 1 and odd numbered cycles”. • The window for performing urine or serum pregnancy test was extended to 7 days. • The start of each cycle was clarified to mean Day 1. • The window for performing the pregnancy test at Screening was extended to 7 days. • Clarified that study visit is to occur on Day 1 of every cycle. Study drug administration was clarified to include combination therapy, if applicable. • Cycle numbers of odd-numbered cycles were added. Added the window for performing the End-of-Treatment visit after starting alternative therapy. • The timeframe for collection of adverse events information was changed from "1 month" to "30 days".

• Changed tivozanib to tivozanib hydrochloride throughout. • Trial objectives and purpose section updated to clarify that protocol AV-951-12-205 was a crossover study and subjects from that study would roll over into protocol AV-951-09-901. • Subject enrollment section was updated to clarify that Interactive Web Response System (IWRS) was implemented for enrollment and management of clinical supplies. • Inclusion criterion #2 was revised to "If female and of childbearing potential, documentation of negative pregnancy test prior to enrollment (i.e. first dose of tivozanib hydrochloride in this protocol)". • Exclusion criterion #1 was updated to "> 4 weeks since discontinuation of study drug treatment on a previous AVEO sponsored clinical trial". • Information on the procedures/parameters to be measured in the study was revised. In addition, removed statement that waivers will be reviewed and approved by the sponsor. • Information on storage condition requirements and administration of tivozanib hydrochloride was updated. • Information on duration of follow up and management of toxicity were revised.

• Clarified information on subjects who were eligible for enrollment in the study under study design and plan description. • Inclusion criterion # 1 was revised. • Exclusion criteria # I was modified. • Concomitant medication section was updated to provide clarification to sites regarding medications/treatments that were permitted per the protocol and to provide guidance on other medications/treatments • As a result of tivozanib hydrochloride not receiving FDA approval for the treatment of RCC, Study AV-951·09-901 was modified to provide long-term tivozanib hydrochloride treatment to those subjects who were tolerating and deriving clinical benefit from it and restrict data collection to safety (adverse/serious adverse events) data only. • Frequency of blood pressure was modified based on length of treatment with tivozanib hydrochloride (< 1 year vs. > I year) • Frequency and description of procedure (hematology, serum chemistries, urinalysis) modified based on length of treatment with tivozanib hydrochloride « 1 year vs. > 1 year) • Thyroid function was added to monitor additional safety of tivozanib hydrochloride • Clarified that efficacy data, prior and concomitant medications were no longer recorded. • Updated to provide clarification regarding the optional use and review of the study drug administration diary during the study • Description of visits and procedures to be performed was modified to reflect only AE and SAE data will be collected and clinical evaluations based on duration of treatment (< 1 yr vs. > 1 yr) • Removed assessment of concomitant medications and imaging scan at the end of treatment visit • Clarified that unscheduled visits were to be performed as clinically indicated per the investigator • Modified to remove concomitant medication assessment at the 30 day follow-up visit. • Updated to reflect that no more than 3 cycles (bottles) of tivozanib hydrochloride would be dispensed at a time.