Tivozanib + Nivolumab for Kidney Cancer

Not currently recruiting at 215 trial locations

Overseen By AVEO Clinical Trials Office

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: AVEO Pharmaceuticals, Inc.

Must be taking: Immune checkpoint inhibitors

Must not be taking: Immune suppressive therapy

Disqualifiers: Autoimmune disease, Uncontrolled hypertension, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: 2

Duration: Approximately 30 months

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine the effectiveness of combining tivozanib with nivolumab compared to using tivozanib alone for individuals with advanced kidney cancer. Tivozanib and nivolumab target cancer cells in different ways, and researchers seek to assess whether their combined use can enhance effectiveness. Participants should have advanced kidney cancer, have undergone one or two prior treatments, and experienced recent cancer progression despite previous treatment. As a Phase 3 trial, this study represents the final step before FDA approval, providing participants an opportunity to contribute to potentially groundbreaking treatment advancements.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. However, it does mention that participants must have recovered from the side effects of previous treatments, which might imply some changes to your current medication regimen.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that both tivozanib and its combination with nivolumab are generally well-tolerated by people with kidney cancer. Studies have found no major differences in side effects between patients taking the combination and those taking tivozanib alone, indicating that neither treatment has worse side effects than the other.

For tivozanib alone, data from large studies with many patients suggest it is safe and tolerable, even for those who have undergone multiple previous treatments. Patients have experienced a consistent safety profile, with predictable and manageable side effects over time.

While nivolumab is not new and has been used for other conditions, its combination with tivozanib did not reveal any new safety concerns. However, adding nivolumab did not improve treatment outcomes for patients in some studies. This suggests that while the combination is safe, it might not offer additional benefits over tivozanib alone in certain cases.

Overall, past research considers these treatments safe for most patients. However, discussing any concerns with doctors before joining a clinical trial is important. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about Tivozanib combined with Nivolumab for kidney cancer because it offers a novel approach by combining a VEGF inhibitor with an immune checkpoint inhibitor. Unlike standard treatments like sunitinib or pazopanib, which primarily target cancer cell growth pathways, this combination aims to both inhibit tumor blood vessel growth and boost the body's immune response against cancer cells. Tivozanib is designed to be highly selective, potentially leading to fewer side effects, while Nivolumab enhances immune system activity, offering a dual attack on the cancer. This innovative combination has the potential to improve outcomes for patients with advanced renal cell carcinoma by tackling the disease from two different angles.

What evidence suggests that this trial's treatments could be effective for advanced kidney cancer?

Research has shown that tivozanib effectively treats advanced kidney cancer. Studies indicate that about one-third of patients experience tumor shrinkage. Long-term evidence suggests that tivozanib remains effective over time for people with advanced kidney cancer. For those who try tivozanib after other treatments, the response rate can reach 62%. In this trial, one group of participants will receive tivozanib alone, while another group will receive a combination of tivozanib and nivolumab, an immune therapy. Both options offer promising treatment paths for patients with advanced kidney cancer. ^{4 6 7 8 9}

Are You a Good Fit for This Trial?

This trial is for adults with advanced kidney cancer who've had 1 or 2 previous treatments, including an immune therapy. They must have clear cell renal carcinoma, measurable disease, be in good physical condition (able to perform daily activities), and use contraception. Excluded are those with active autoimmune diseases, uncontrolled high blood pressure, more than one prior immune therapy in the metastatic setting, severe past reactions to immune therapies, certain treatment sequences or over two lines of prior therapy.

Inclusion Criteria

I have recovered from previous treatment side effects to my normal or mild condition.

My kidney cancer has been confirmed with a lab test.

You have a measurable disease according to specific medical guidelines.

Exclusion Criteria

I've had a TKI as my first treatment and an ICI as my second for advanced cancer.

My high blood pressure is not under control.

I have an active autoimmune disease or stopped IO therapy due to side effects.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

4 weeks

1 visit (in-person)

Treatment

Participants receive tivozanib with or without nivolumab for 3 weeks followed by 1 week off, repeated in cycles until disease progression or unacceptable toxicity

Approximately 30 months

Monthly visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

30 days

1 visit (in-person)

Long-term Follow-up

Participants are monitored for overall survival and progression-free survival

Approximately 42 months

What Are the Treatments Tested in This Trial?

Interventions

• Nivolumab
• Tivozanib

Trial Overview The study compares a combination of Tivozanib (a drug that targets tumor blood vessels) and Nivolumab (an immunotherapy) versus just Tivozanib alone in patients with advanced Renal Cell Carcinoma. It aims to see if adding Nivolumab improves outcomes for patients who have already tried other treatments.

How Is the Trial Designed?

Group I: Tivozanib in Combination with Nivolumab Experimental Treatment 2 Interventions

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.

Group II: Tivozanib Experimental Treatment 1 Intervention

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.

Nivolumab is already approved in United States, European Union, Canada, Switzerland for the following indications:

Approved in United States as Opdivo for:

• Advanced or metastatic gastric cancer
• Gastroesophageal junction cancer
• Esophageal adenocarcinoma
• Melanoma
• Non-small cell lung cancer
• Renal cell carcinoma
• Hodgkin lymphoma
• Head and neck squamous cell carcinoma
• Urothelial carcinoma
• Colorectal cancer
• Hepatocellular carcinoma
• Esophageal squamous cell carcinoma

Approved in European Union as Opdivo for:

• Melanoma
• Non-small cell lung cancer
• Renal cell carcinoma
• Hodgkin lymphoma
• Head and neck squamous cell carcinoma
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Gastroesophageal junction cancer
• Esophageal adenocarcinoma

Approved in Canada as Opdivo for:

• Melanoma
• Non-small cell lung cancer
• Renal cell carcinoma
• Hodgkin lymphoma
• Head and neck squamous cell carcinoma
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Gastroesophageal junction cancer
• Esophageal adenocarcinoma

Approved in Switzerland as Opdivo for:

• Melanoma
• Non-small cell lung cancer
• Renal cell carcinoma
• Hodgkin lymphoma
• Head and neck squamous cell carcinoma
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Gastroesophageal junction cancer
• Esophageal adenocarcinoma

Who Is Running the Clinical Trial?

AVEO Pharmaceuticals, Inc.

Lead Sponsor

Trials

46

Recruited

4,000+

Parexel

Industry Sponsor

Trials

322

Recruited

137,000+

Peyton Howell

Parexel

Chief Executive Officer

Master of Healthcare Administration from The Ohio State University, Bachelor of Arts in Health Communications from the University of Illinois

Dr. Austin Smith

Parexel

Chief Medical Officer since 2023

MD from the Royal College of Surgeons in Ireland

Bristol-Myers Squibb

Industry Sponsor

Trials

2,731

Recruited

4,127,000+

Headquarters

New York City, USA

Known For

Oncology & Cardiovascular

Top Products

Eliquis, Opdivo, Revlimid, Orencia

Christopher Boerner

Bristol-Myers Squibb

Chief Executive Officer since 2023

PhD in Business Administration from the Haas School of Business, University of California, Berkeley; BA in Economics and History from Washington University in St. Louis

Deepak L. Bhatt

Bristol-Myers Squibb

Chief Medical Officer since 2024

MD from Yale University; MSc in Clinical Epidemiology from the University of Pennsylvania

Published Research Related to This Trial

A 65-year-old man with advanced renal cell carcinoma achieved a remarkable reduction in metastasis after receiving nivolumab as the fifth systemic therapy, following treatment with angiogenesis inhibitors and interferon-α.

The patient experienced a pathological complete response, with no cancer cells found after adrenalectomy, and remains healthy 20 months post-surgery, highlighting the potential efficacy of nivolumab in advanced renal cell carcinoma cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pathological complete response after nivolumab therapy following angiogenesis inhibitors in a patient with metastatic renal cell carcinoma. Hagimoto, H., Kashima, S., Doi, K., et al.[2022]

In a study of 91 patients with metastatic renal cell carcinoma (mRCC), nivolumab showed significant improvements in overall survival, with a median survival of 25.2 months for the highest dose (10 mg/kg) and not reached for treatment-naïve patients.

Nivolumab treatment led to substantial increases in tumor-associated lymphocytes and changes in chemokine levels, indicating its immunomodulatory effects, while no new safety concerns were identified.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immunomodulatory Activity of Nivolumab in Metastatic Renal Cell Carcinoma. Choueiri, TK., Fishman, MN., Escudier, B., et al.[2022]

Tivozanib is a highly selective VEGFR inhibitor that has been approved in Europe for treating advanced renal cell carcinoma (RCC) in adults, both as a first-line treatment and after prior cytokine therapy.

The drug is currently being developed in other countries for advanced RCC and solid tumors, indicating its potential for broader use in cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tivozanib: First Global Approval. Kim, ES.[2018]

In a real-world analysis of adverse events from two combination therapies for advanced renal cell carcinoma, cabozantinib (CAB) plus nivolumab (NIVO) showed higher incidence rates of seven types of toxicities compared to ipilimumab (IPI) plus NIVO.

Conversely, IPI + NIVO was associated with higher rates of three types of toxicities and had a greater incidence of serious adverse events, suggesting that both therapies have distinct safety profiles that can guide treatment decisions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse Events of Cabozantinib Plus Nivolumab Versus Ipilimumab Plus Nivolumab. Blas, L., Shiota, M., Tsukahara, S., et al.[2023]

Nivolumab (Opdivo®) has been established as an effective second-line treatment for metastatic renal cell carcinoma (mRCC), showing improved overall survival (26 months vs. 19.7 months) and response rates compared to Everolimus, based on the CheckMate 025 trial with 1,080 participants.

The combination of Nivolumab and Ipilimumab has demonstrated a significantly higher objective response rate (42% vs. 27%) and better overall survival in intermediate and high-risk patients compared to Sunitinib, while also improving quality of life, despite an increase in immune-related adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Immunotherapy for renal cell carcinoma - current status]. Grimm, MO., Foller, S.[2019]

Nivolumab, when combined with ipilimumab, significantly improves overall survival (OS) and progression-free survival (PFS) in patients with advanced renal cell carcinoma (RCC), based on a meta-analysis of three high-quality randomized controlled trials involving 2550 patients.

The treatment with nivolumab did not lead to an increase in adverse events, indicating a manageable safety profile for patients undergoing this therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and Safety of Nivolumab for Advanced Renal Cell Carcinoma: A Systematic Review and Meta-Analysis. Zhang, S., Xu, X., Chen, J., et al.[2022]

In a study of 69 patients with metastatic renal cell carcinoma treated with nivolumab plus ipilimumab, those who experienced immune-related adverse events (irAEs) had significantly better overall survival (OS) and progression-free survival compared to those without irAEs, suggesting that irAEs may be a positive indicator of treatment response.

The study identified three key factors influencing OS: the presence of irAEs, C-reactive protein levels, and performance status, indicating that monitoring these factors could help predict patient outcomes in mRCC treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prognostic Impact of Immune-Related Adverse Events as First-Line Therapy for Metastatic Renal Cell Carcinoma Treated With Nivolumab Plus Ipilimumab: A Multicenter Retrospective Study. Nukaya, T., Takahara, K., Yoshizawa, A., et al.[2023]

In a study of 389 patients with metastatic renal cell cancer (mRCC) treated with nivolumab, the treatment showed a 23.1% objective response rate and a median progression-free survival of 4.5 months, indicating its efficacy in this patient population.

The safety profile was favorable, with no treatment-related deaths and only 5.7% of patients discontinuing treatment due to adverse events, suggesting that nivolumab is a safe option for patients, including those who are elderly or have previously received multiple therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of nivolumab for metastatic renal cell carcinoma: real-world results from an expanded access programme. De Giorgi, U., Cartenì, G., Giannarelli, D., et al.[2022]

In a phase 3 trial involving 651 patients with untreated advanced renal-cell carcinoma, the combination of nivolumab and cabozantinib significantly improved progression-free survival (16.6 months) compared to sunitinib (8.3 months), with a hazard ratio of 0.51, indicating a 49% reduction in the risk of disease progression or death.

Patients receiving nivolumab plus cabozantinib also had a higher overall survival rate at 12 months (85.7%) compared to those on sunitinib (75.6%), and a greater objective response rate (55.7% vs. 27.1%), although adverse events were common in both groups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab plus Cabozantinib versus Sunitinib for Advanced Renal-Cell Carcinoma. Choueiri, TK., Powles, T., Burotto, M., et al.[2022]

In the phase 3 TIVO-3 trial, tivozanib (Fotivda) demonstrated a significant improvement in progression-free survival (PFS) compared to sorafenib (Nexavar) for patients with highly relapsed or refractory metastatic renal cell carcinoma (RCC).

These results suggest that tivozanib may be a more effective treatment option for patients with advanced RCC who have not responded to previous therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Final Data Analysis Supports Tivozanib as Superior Treatment for Patients With RCC. Wright, KM.[2021]

In a phase Ib/II study involving 25 patients with metastatic renal cell carcinoma (RCC), the combination of tivozanib and nivolumab demonstrated a high objective response rate of 56% and a disease control rate of 96%, indicating strong antitumor efficacy.

The treatment was generally well-tolerated, with 80% of patients experiencing treatment-related grade 3/4 adverse events, but the median progression-free survival was promising at 18.9 months, supporting further investigation of this combination therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

TiNivo: safety and efficacy of tivozanib-nivolumab combination therapy in patients with metastatic renal cell carcinoma. Albiges, L., Barthélémy, P., Gross-Goupil, M., et al.[2021]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10066464/

Current Status of Tivozanib in the Treatment of Patients With ... The overall response rate (ORR) was also statistically higher for tivozanib (33.1% vs. 23.3%, p=0.014) [13]. Table 1. Efficacy of tivozanib in ...

2. fotivda.com fotivda.com/effectiveness/

How FOTIVDA® (tivozanib) May Help Treat Advanced RCC The effectiveness and safety of FOTIVDA was proven in a large clinical study of people (350 people in total) with relapsed or refractory advanced kidney cancer ...

3. esmo.org esmo.org/oncology-news/efficacy-of-tivozanib-monotherapy-in-the-post-ici-setting-among-patients-with-advanced-renal-cell-cancer

Efficacy of Tivozanib Monotherapy in the Post-ICI Setting ... With a median follow-up of 19 months, the combination showed an overall response rate (ORR) of 62%; the median PFS was not reached. Hypertension ...

4. onclive.com onclive.com/view/1-34-mg-dose-of-tivozanib-is-more-efficacious-than-reduced-0-89-mg-dose-in-rcc

1.34-mg Dose of Tivozanib Is More Efficacious Than ... An ER model analysis showed that 1.34 mg of tivozanib provided a greater decrease in tumor size and may be more tolerable than an 0.89-mg dose in RCC.

5. urologytimes.com urologytimes.com/view/long-term-data-highlight-sustained-efficacy-of-tivozanib-in-advanced-kidney-cancer

Long-term data highlight sustained efficacy of tivozanib in ... Long-term results showed continued efficacy and safety with tivozanib (Fotivda) in patients with relapsed or refractory advanced renal cell carcinoma (RCC).

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11224966/

Efficacy, Safety, and Tolerability of Tivozanib in Heavily ... This article describes the outcomes of patients who were treated with tivozanib for advanced renal cell carcinoma (RCC) and provides data to ...

7. ascopubs.org ascopubs.org/doi/10.1200/JCO.2024.42.4_suppl.419

Efficacy, safety, and tolerability of tivozanib (TIVO) in ... Efficacy, safety, and tolerability of tivozanib (TIVO) in heavily pretreated patients (pts) with advanced clear-cell renal cell carcinoma (ccRCC) ...

8. academic.oup.com academic.oup.com/oncolo/article/29/3/254/7585810

Long-Term Survival in Patients With Relapsed/Refractory ... Tivozanib demonstrated a consistent safety profile and long-term survival benefit in patients with R/R advanced RCC who were alive and progression free at 12 ...

9. aveooncology.com aveooncology.com/aveo-oncology-announces-publication-of-long-term-survivalin-patients-with-relapsed-refractory-advanced-renal-cellcarcinoma-treated-with-tivozanib-analysis-of-the-phase-iiitivo-3-trial-in-the-oncologi/

Analysis of the Phase III TIVO-3 Trial in The Oncologist The Oncologist has published a post-hoc analysis of long-term progression free survival, overall survival and safety data from the Phase 3 TIVO-3 trial.