Tivozanib + Nivolumab for Advanced Kidney Cancer

Recruiting at 4 trial locations

Overseen By Eric Jonasch, M D

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: M.D. Anderson Cancer Center

Must not be taking: CYP3A inducers, Corticosteroids

Disqualifiers: Uncontrolled hypertension, Autoimmune disorders, HIV, others

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

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: 1

Duration: 4 weeks per cycle

48 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial examines whether combining tivozanib, a daily oral tablet, and nivolumab, an IV medication given every four weeks, can control advanced kidney cancer without clear cell features. It evaluates the effectiveness of these drugs together for individuals with a more challenging type of kidney cancer. Suitable candidates for this trial include those with advanced kidney cancer confirmed by a doctor who have undergone no more than one prior treatment. As a Phase 2 trial, this research measures the treatment's effectiveness in an initial, smaller group, providing participants an opportunity to contribute to significant advancements in cancer therapy.

Will I have to stop taking my current medications?

If you have received previous systemic therapy, you will need to stop and wait for a 'washout period' (time without taking certain medications) of 5 half-lives or 21 days, whichever is shorter. The protocol does not specify other medication restrictions, but you should discuss your current medications with the study team.

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

Research has shown that patients generally tolerate the combination of tivozanib and nivolumab well. A study comparing this combination to tivozanib alone in patients with advanced kidney cancer found similar side effects in both groups. Common side effects included tiredness, diarrhea, and high blood pressure, mostly mild to moderate.

Patients reported no major differences in overall well-being, whether they received the combination or just tivozanib. This suggests that adding nivolumab did not noticeably increase side effects.

Overall, current data indicates that the safety of using tivozanib and nivolumab together is promising. While side effects can occur, they are similar to those expected from similar treatments and are usually manageable. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of Tivozanib and Nivolumab for advanced kidney cancer because it brings together two powerful mechanisms. Tivozanib is a targeted therapy that blocks VEGF receptors, which are crucial for blood vessel growth in tumors, potentially starving the cancer. Meanwhile, Nivolumab is an immunotherapy that boosts the body's immune response to fight cancer cells. This dual approach of starving the tumor while enhancing immune attack could offer a more effective treatment option compared to current therapies, which typically involve monotherapies like sunitinib or pazopanib.

What evidence suggests that the combination of tivozanib and nivolumab could be effective for advanced kidney cancer?

Research has shown that combining tivozanib and nivolumab may help treat advanced kidney cancer. In this trial, participants will receive both drugs together. One study found that patients taking both drugs experienced stable cancer for an average of nearly six months. Although this combination did not significantly improve patient well-being compared to tivozanib alone, it remains a viable option. Tivozanib blocks signals that tumors need to grow, while nivolumab helps the immune system attack cancer cells. This two-pronged approach aims to control the cancer more effectively. ^{1 2 3 4 6}

Who Is on the Research Team?

Eric Jonasch, MD

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

Adults with advanced non-clear cell renal cell carcinoma, who have adequate organ function and no more than one prior systemic therapy. They must not be pregnant or breastfeeding, agree to use contraception, and cannot have uncontrolled hypertension or a history of severe allergic reactions to similar drugs.

Inclusion Criteria

I can care for myself but may not be able to do heavy physical work.

I've had only one type of systemic therapy for my cancer, which could include immunotherapy or targeted therapy.

My blood counts and liver/kidney functions are within normal ranges.

Exclusion Criteria

You have an autoimmune disorder, except for some specific conditions like vitiligo, alopecia, stable hypothyroidism, or certain chronic skin conditions that don't need strong medication.

Has evidence of any other medical conditions, psychiatric condition, physical examination or laboratory findings that may interfere with the planned treatment, affect subject compliance or place the subject at high risk from treatment-related complications in the opinion of the local principal investigator (PI)

I have previously been treated with nivolumab.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive tivozanib tablets daily for 21 days and nivolumab intravenously every 4 weeks

4 weeks per cycle

1 visit (in-person) every 4 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Nivolumab
• Tivozanib

Trial Overview The trial is testing the combination of Tivozanib (a tyrosine kinase inhibitor) and Nivolumab (an immunotherapy agent) in patients with advanced kidney cancer that's not the usual 'clear cell' type. The goal is to see if this combo can control the disease better.

How Is the Trial Designed?

Group I: Combination Tivozanib and Nivolumab Experimental Treatment 2 Interventions

Nivolumab by vein over about 60 minutes every 4 weeks (Day 1 of each cycle). Tivozanib tablets by mouth 1 time every day for 21 days (Days 1-21 of each cycle), and then no tablets on Days 22-28 of each cycle.

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?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

AVEO Pharmaceuticals, Inc.

Industry Sponsor

Trials

46

Recruited

4,000+

Published Research Related to This Trial

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]

The CLEAR trial showed that the combination of lenvatinib and pembrolizumab significantly improves progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) compared to sunitinib in treatment-naïve metastatic clear-cell renal cell carcinoma.

Combination therapies involving immune checkpoint inhibitors, such as cabozantinib plus nivolumab and axitinib plus pembrolizumab, also demonstrated similar survival benefits and improved quality of life, making them recommended first-line treatments for advanced kidney cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The 2021 Updated European Association of Urology Guidelines on Renal Cell Carcinoma: Immune Checkpoint Inhibitor-based Combination Therapies for Treatment-naive Metastatic Clear-cell Renal Cell Carcinoma Are Standard of Care. Bedke, J., Albiges, L., Capitanio, U., et al.[2022]

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 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]

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 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]

Tivozanib is a newly approved treatment for advanced renal cell carcinoma (RCC) that targets multiple vascular endothelial growth factor receptors (VEGFR-1, -2, and -3), showing a promising safety profile and clinical benefits for patients who have already undergone multiple therapies.

The ongoing TINIVO-2 study is exploring the combination of tivozanib with nivolumab, which could potentially enhance treatment options for patients who have not responded to immune checkpoint inhibitors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tivozanib for the treatment of advanced renal cell carcinoma. Chatzkel, J., Ramnaraign, B., Sonpavde, G.[2022]

Nivolumab, when combined with ipilimumab, significantly improves overall survival rates in previously untreated advanced renal cell carcinoma (RCC), achieving an 18-month survival rate of 75% compared to 60% with sunitinib alone.

The combination therapy also results in a higher objective response rate of 42% versus 27% for sunitinib, indicating that immune checkpoint inhibitors are becoming a promising first-line treatment option for metastatic RCC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Frontline immunotherapy treatment with nivolumab and ipilimumab in metastatic renal cell cancer: a new standard of care. Nizam, A., Aragon-Ching, JB.[2020]

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 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]

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]

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 a study of 264 patients with advanced renal cell carcinoma (RCC) treated with nivolumab, the median overall survival was 18.7 months, and the objective response rate was 18.6%, indicating that nivolumab is an effective treatment option for this patient population.

The study identified potential predictive biomarkers, such as an increase in eosinophils by week 8, which was associated with improved overall survival and progression-free survival, suggesting that monitoring eosinophil levels could help predict treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-world Data of Nivolumab for Patients With Advanced Renal Cell Carcinoma in the Netherlands: An Analysis of Toxicity, Efficacy, and Predictive Markers. Verhaart, SL., Abu-Ghanem, Y., Mulder, SF., et al.[2021]

Citations

1. thelancet.com thelancet.com/journals/lancet/article/PIIS0140-6736(24)01758-6/abstract

Tivozanib plus nivolumab versus tivozanib monotherapy in ... This study aimed to assess clinical outcomes of tivozanib–nivolumab versus tivozanib monotherapy in patients with metastatic renal cell ...

2. ascopubs.org ascopubs.org/doi/10.1200/JCO.2025.43.5_suppl.459

Patient-reported outcomes (PROs) for tivozanib (TIVO) ... In the intent-to-treat population, the median progression-free survival was 5.7 months (95% CI, 4.0-7.4) with TIVO + NIVO and 7.4 months (5.6- ...

3. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39284329/

results of the phase 3 TiNivo-2 Study - PubMed This study aimed to assess clinical outcomes of tivozanib-nivolumab versus tivozanib monotherapy in patients with metastatic renal cell carcinoma

4. onclive.com onclive.com/view/tivozanib-elicits-similar-pros-with-or-without-nivolumab-in-advanced-clear-cell-rcc

Tivozanib Elicits Similar PROs With or Without Nivolumab ... No significant differences in PROs were shown between the tivozanib/nivolumab and tivozanib monotherapy arms in patients with advanced clear cell RCC.

5. urotoday.com urotoday.com/conference-highlights/esmo-2024/esmo-2024-kidney-cancer/154745-esmo-2024-tivozanib-nivolumab-vs-tivozanib-monotherapy-in-patients-with-rcc-following-1-or-2-prior-therapies-including-an-immune-checkpoint-inhibitor-results-of-the-phase-iii-tinivo-2-study.html

Results of the Phase III TiNivo-2 Study A sample size of 343 patients with 220 events provided ≥80% power to detect a 50% improvement in progression free survival, 12 months versus 8 ...

6. aveooncology.com aveooncology.com/aveo-oncology-an-lg-chem-company-announces-phase-3-renal-cell-carcinoma-clinical-trial-tinivo-2-results/

AVEO Oncology, an LG Chem company, Announces ... The TiNivo-2 Phase 3 clinical trial in patients with advanced metastatic renal cell carcinoma (RCC) whose tumors had progressed following prior immune ...