Study to Compare Tivozanib in Combination With Nivolumab to Tivozanib Monotherapy in Subjects With Renal Cell Carcinoma

• ClinicalTrials.gov Identifier: NCT04987203
• Recruitment Status: Recruiting
• First Posted: August 3, 2021
• Last Update Posted: March 20, 2023
• Sponsor: AVEO Pharmaceuticals, Inc.
• Collaborators: Parexel; Bristol-Myers Squibb
• Information provided by (Responsible Party): AVEO Pharmaceuticals, Inc.

Tracking Information

• First Submitted Date: July 23, 2021
• First Posted Date: August 3, 2021
• Last Update Posted Date: March 20, 2023
• Actual Study Start Date: September 9, 2021
• Estimated Primary Completion Date: August 1, 2024 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: July 23, 2021)

Progression free survival [ Time Frame: until progressive disease [PD] (Approximately 30 months) ]

Comparison of the PFS of tivozanib in combination with nivolumab to tivozanib in subjects with RCC who have progressed following 1 or 2 lines of therapy. PFS is defined as the time from randomization to first documentation of objective tumor progression (progressive disease [PD], radiological) according to Response Evaluation Criteria In Solid Tumors (RECIST), or death due to any reasons whichever comes first.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: July 23, 2021)

• Overall Survival [ Time Frame: From Screening (Days -28 to -1) until death (Approximately 42 months) ]
  Comparsion of the OS of subjects randomized to treatment with tivozanib in combination with nivolumab compared to tivozanib. OS is defined as the time from the date of randomization to date of death due to any cause.
• Objective Response Rate [ Time Frame: From Screening (Days -28 to -1) until PD (Approximately 30 months) ]
  Comparison of ORR of subjects randomized to treatment with tivozanib in combination with nivolumab compared to tivozanib. ORR is defined as the proportion of subjects with confirmed complete response or confirmed partial response according to RECIST relative to the total population of randomized subjects.
• Duration of Response [ Time Frame: From Screening (Days -28 to -1) until PD or death (Approximately 30 months) ]
  Comparison of DoR of subjects randomized to treatment with tivozanib in combination with nivolumab compared to tivozanib. DoR is defined as the time from the first documentation of objective tumor response to the first documentation of objective tumor progression or to death due to any cause.
• Number of subjects with serious and non-serious adverse events [ Time Frame: From Screening (Day -28 to Day -1) to Follow-up visit (30 days after last dose of study drug ± 7 days) ]
  Assessment of the safety and tolerability of tivozanib in combination with nivolumab compared to tivozanib.

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Study to Compare Tivozanib in Combination With Nivolumab to Tivozanib Monotherapy in Subjects With Renal Cell Carcinoma
• Official Title: TiNivo-2: A Phase 3, Randomized, Controlled, Multicenter, Open-label Study to Compare Tivozanib in Combination With Nivolumab to Tivozanib Monotherapy in Subjects With Renal Cell Carcinoma Who Have Progressed Following One or Two Lines of Therapy Where One Line Has an Immune Checkpoint Inhibitor
• Brief Summary: This study will be comparing tivozanib in combination with nivolumab to tivozanib alone in subjects with advanced Renal Cell Carcinoma (RCC) who have had 1 or 2 prior lines of therapy, one of which was an Immune Checkpoint Inhibitor (ICI).

Detailed Description

This will be an open-label, randomized, controlled, multicenter, multi-national, parallel-arm study. The study is designed to compare the progression free survival (PFS), overall survival (OS), Objective response rate (ORR), duration of response (DoR), and safety of tivozanib and the combination of tivozanib with nivolumab.

Approximately 326 subjects with refractory advanced RCC at approximately 190 sites will be randomized in a 1:1 ratio to treatment with tivozanib plus nivolumab (163 subjects) or tivozanib (163 subjects). Subjects will be randomly assigned to a treatment.

Subjects will receive 1.34 mg/day (monotherapy arm) or 0.89mg/day (combination arm) of tivozanib once daily (QD) for 3 weeks followed by 1 week off study drug. One cycle will be defined as 4 weeks: 3 weeks on treatment and 1 week off treatment. Subjects who receive nivolumab will be infused with 1 treatment of nivolumab at specified dose on specified days of each Cycle.

Subjects with documented stable disease or an objective response may continue to receive both tivozanib and nivolumab therapy at the same dose and schedule until progression as long as the tolerability is acceptable. Nivolumab will be discontinued in all subjects after 2 years. A Safety Follow-up Visit will be performed 30 days (± 7 days) after the last dose of study drug.

• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Renal Cell Carcinoma

Intervention

• Drug: Tivozanib
  Tivozanib will be administered orally.
• Drug: Nivolumab
  Nivolumab will be administered via intravenous infusion.

Study Arms

• Experimental: Tivozanib in Combination with Nivolumab
  Subjects with advanced RCC will receive 0.89 mg of tivozanib once daily (QD) for 3 weeks followed by 1 week off study drug and nivolumab every 4 weeks on Day 1 of each Cycle, until disease progression or unacceptable toxicities occur, other withdrawal criteria are met, or completion of 2 years of treatment [for nivolumab] whichever occurs first.
  Interventions:

  • Drug: Tivozanib
  • Drug: Nivolumab
• Experimental: Tivozanib
  Subjects with advanced RCC will receive 1.34 mg of tivozanib once daily (QD) for 3 weeks followed by 1 week off study drug until disease progression or unacceptable toxicities occur, or other withdrawal criteria are met.
  Intervention: Drug: Tivozanib

• Publications *: Yang Y, Psutka SP, Parikh AB, Li M, Collier K, Miah A, Mori SV, Hinkley M, Tykodi SS, Hall E, Thompson JA, Yin M. Combining immune checkpoint inhibition plus tyrosine kinase inhibition as first and subsequent treatments for metastatic renal cell carcinoma. Cancer Med. 2022 Aug;11(16):3106-3114. doi: 10.1002/cam4.4679. Epub 2022 Mar 18.

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: July 23, 2021): 326
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: August 1, 2025
• Estimated Primary Completion Date: August 1, 2024 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Radiographic disease progression during or following at least 6 weeks of treatment with ICI for locally advanced or metastatic RCC with a clear cell component either in first- or second-line treatment.
• Subjects must have recovered from the adverse events of prior therapy or returned to baseline.
• Histologically or cytologically confirmed RCC with a clear cell component.
• Measurable disease per RECIST criteria Version 1.1.
• Eastern Cooperative Oncology Group performance status of 0 or 1.
• All participants must follow protocol defined contraceptive measures.

Exclusion Criteria:

• More than 2 prior lines of therapy in the advanced or metastatic setting.
• History of life-threatening toxicity related to prior immune therapy.
• Active, known, or suspected autoimmune disease as well as those that required discontinuation of prior immuno-oncological (IO) therapy due to immune mediated AEs.
• Uncontrolled hypertension.
• More than 1 prior line of therapy with a checkpoint inhibitor in the metastatic setting.
• Subjects on immune suppressive therapy for organ transplant or subjects with a history of genetic or acquired immune suppression disease such as human immunodeficiency virus (HIV) [Patients with HIV who have CD4+ T-cell counts >350 cells/µL, without a history of acquired immune deficiency syndrome (AIDS)-defining opportunistic infections, and are on established antiretroviral therapy which does not include a cytochrome P450 (CYP)3A4 inducer, for at least 4 weeks and have an HIV viral load less than 400 copies/mL, are eligible].
• History of clinically significant interstitial lung disease or current non-infectious pneumonitis.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 130 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: AVEO Clinical Trials Office; (857) 400-0101; clinical@aveooncology.com

• Listed Location Countries: Argentina, Australia, Belgium, Brazil, Canada, Chile, Czechia, France, Germany, Italy, Mexico, Poland, Portugal, Spain, United Kingdom, United States

Administrative Information

• NCT Number: NCT04987203
• Other Study ID Numbers: AV-951-20-304
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: AVEO Pharmaceuticals, Inc.
• Original Responsible Party: Same as current
• Current Study Sponsor: AVEO Pharmaceuticals, Inc.
• Original Study Sponsor: Same as current

Collaborators

• Parexel
• Bristol-Myers Squibb

• Investigators: Not Provided
• PRS Account: AVEO Pharmaceuticals, Inc.
• Verification Date: March 2023