Zanzalintinib Combinations for Renal Cell Carcinoma

Recruiting at 16 trial locations

Overseen By Backup or International

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Exelixis

Must not be taking: Oral anticoagulants, Live vaccines

Disqualifiers: Brain metastases, Radiation complications, others

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

Compensation: Varies

Number of Visits: Unknown

25 Participants Needed

Trial Summary

What is the purpose of this trial?

The goal of this clinical trial is to learn about the safety and preliminary antitumor activity of zanzalintinib in combination with AB521 (doublet) and in combination with AB521 plus nivolumab (triplet) in participants with advanced ccRCC or other advanced solid tumors. The main questions it aims to answer are: * The recommended doses (RDs) * The safety and tolerability * The PK and the preliminary efficacy

Do I need to stop my current medications to join the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, it does mention that participants cannot be on certain anticoagulants (blood thinners) except for specific cases. It's best to discuss your current medications with the trial team.

What data supports the effectiveness of the drug combination for renal cell carcinoma?

Research shows that combinations of drugs like nivolumab and cabozantinib are effective for treating advanced kidney cancer, with patients experiencing more and longer-lasting responses compared to other treatments. Additionally, studies have shown that these combinations can lead to a reduction in tumor size and longer periods without the disease getting worse. ^{1 2 3 4 5}

What safety data exists for Zanzalintinib combinations in renal cell carcinoma treatment?

Safety data for combinations involving Nivolumab, which is part of the Zanzalintinib combinations, show that there are adverse events (side effects) when used with other drugs like Cabozantinib and Ipilimumab. These side effects are important to consider, even though the specific safety data for Zanzalintinib itself is not detailed in the available research. ^{1 6 7 8 9}

What makes the Zanzalintinib combination drug unique for treating renal cell carcinoma?

The Zanzalintinib combination drug is unique because it combines Zanzalintinib (a VEGFR tyrosine kinase inhibitor) with Nivolumab (an immune checkpoint inhibitor), potentially offering a novel approach by targeting both tumor growth and immune response. This combination may provide a new option for patients, especially since similar combinations have shown benefits in progression-free survival and overall response rates in other trials. ^{1 2 3 5 10}

Eligibility Criteria

This trial is for adults with advanced clear cell renal cell carcinoma (ccRCC) or other solid tumors. Participants should not have had previous treatments that are similar to the drugs in this study and must be able to perform daily activities with minimal assistance.

Inclusion Criteria

My kidney cancer cannot be removed by surgery and is advanced.

I have recovered from previous treatment side effects, or they are minor and stable.

I have never been treated with HIF-2α inhibitors.

Exclusion Criteria

I have not received a live vaccine in the last 30 days.

I haven't had radiation for bone metastases in the last 2 weeks or any other radiation in the last 4 weeks.

My brain metastases have been treated and stable for over 4 weeks.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose-finding

Participants receive zanzalintinib in combination with AB521 or AB521 plus nivolumab to determine recommended doses

8-12 weeks

Expansion

Participants receive the determined doses of zanzalintinib in combination with AB521 or AB521 plus nivolumab to evaluate safety and efficacy

12-24 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4-8 weeks

Treatment Details

Interventions

• AB521
• Nivolumab
• Zanzalintinib

Trial Overview The trial is testing the safety and initial effectiveness of a new drug combo: Zanzalintinib with AB521, and Zanzalintinib with AB521 plus Nivolumab. It's looking at what doses are safe, how well patients tolerate the treatment, how their bodies process it, and if it works against cancer.

Participant Groups

Group I: Expansion Cohort 2: zanzalintinib + AB521 + nivolumab Experimental Treatment 3 Interventions

Participants with ccRCC will receive zanzalintinib + AB521 + nivolumab

Group II: Expansion Cohort 1: Zanzalintinib + AB521 Experimental Treatment 2 Interventions

Participants with ccRCC will receive zanzalintinib + AB521

Group III: Dose-finding Cohort B: zanzalintinib + AB521 + nivolumab Experimental Treatment 3 Interventions

Participants with ccRCC will receive zanzalintinib + AB521 + nivolumab

Group IV: Dose-finding Cohort A: Zanzalintinib + AB521 Experimental Treatment 2 Interventions

Participants with solid tumors will receive zanzalintinib + AB521

Who Is Running the Clinical Trial?

Exelixis

Lead Sponsor

Trials

126

Recruited

20,500+

Michael M. Morrissey

Exelixis

Chief Executive Officer since 2010

PhD in Chemistry from Harvard University, BSc in Chemistry from the University of Wisconsin

Vicki L. Goodman

Exelixis

Chief Medical Officer since 2022

MD

Arcus Biosciences, Inc.

Industry Sponsor

Trials

44

Recruited

7,500+

Findings from Research

Combining VEGFR tyrosine kinase inhibitors with immune checkpoint blockers, like cabozantinib with nivolumab or axitinib with pembrolizumab, is now a standard treatment for advanced renal cell carcinoma, showing promising efficacy in clinical trials.

In silico drug modeling suggests that while these combinations are effective, the necessity of using both mechanisms may vary among patients, highlighting the potential for personalized treatment strategies based on tumor profiling.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

In silico modeling of combination systemic therapy for advanced renal cell carcinoma. Kotecha, RR., Hsu, DJ., Lee, CH., et al.[2023]

In a phase III trial, the combination of nivolumab and ipilimumab resulted in a higher response rate (over 41%) compared to sunitinib (26.5%) in patients with intermediate or high-risk renal cell carcinoma.

Patients treated with the immunotherapy combination not only had longer progression-free survival but also experienced fewer side effects, indicating a potentially safer and more effective treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Checkpoint Inhibitor Combo Effective for RCC. [2019]

In a phase II trial involving 47 patients with advanced non-clear-cell renal cell carcinoma, the combination of cabozantinib and nivolumab showed a promising objective response rate of 47.5% in patients with papillary, unclassified, or translocation-associated RCC, along with a median progression-free survival of 12.5 months.

The treatment was less effective in chromophobe RCC, with no objective responses observed, highlighting the need for further research into genomic predictors of response, particularly mutations like NF2 and FH that were associated with better outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II Trial of Cabozantinib Plus Nivolumab in Patients With Non-Clear-Cell Renal Cell Carcinoma and Genomic Correlates. Lee, CH., Voss, MH., Carlo, MI., et al.[2023]

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]

A 52-year-old male with a large inoperable tumor in a horseshoe kidney achieved a major partial response to neoadjuvant therapy with nivolumab and cabozantinib, allowing for successful radical tumor resection and maintaining mild renal function post-treatment.

Despite experiencing hepatotoxicity that led to early withdrawal of nivolumab, the combination of immune checkpoint inhibitors and tyrosine kinase inhibitors shows promise as a neoadjuvant treatment strategy for advanced renal cell carcinoma, particularly in challenging cases like horseshoe kidneys.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neoadjuvant nivolumab and cabozantinib in advanced renal cell carcinoma in a horseshoe kidney - how to achieve a safe and radical resection? a case report and review of the literature. Zemankova, A., Studentova, H., Kopova, A., et al.[2023]

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, 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 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 52 patients with metastatic renal cell carcinoma treated with nivolumab plus ipilimumab, the 1-year progression-free survival rate was 55% and the overall survival rate was 75%, indicating promising efficacy of this treatment combination.

The treatment was associated with a 39% objective response rate, and while 69% of patients experienced immune-related adverse events, the incidence of severe events was lower compared to previous studies, suggesting a favorable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of first-line nivolumab plus ipilimumab in patients with metastatic renal cell carcinoma: A multicenter retrospective study. Tanaka, T., Hatakeyama, S., Numakura, K., et al.[2021]

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]

References

1. England pubmed.ncbi.nlm.nih.gov

In silico modeling of combination systemic therapy for advanced renal cell carcinoma. [2023]

2. United States pubmed.ncbi.nlm.nih.gov

Checkpoint Inhibitor Combo Effective for RCC. [2019]

3. United States pubmed.ncbi.nlm.nih.gov

Phase II Trial of Cabozantinib Plus Nivolumab in Patients With Non-Clear-Cell Renal Cell Carcinoma and Genomic Correlates. [2023]

4. Australia pubmed.ncbi.nlm.nih.gov

Pathological complete response after nivolumab therapy following angiogenesis inhibitors in a patient with metastatic renal cell carcinoma. [2022]

5. Switzerland pubmed.ncbi.nlm.nih.gov

Neoadjuvant nivolumab and cabozantinib in advanced renal cell carcinoma in a horseshoe kidney - how to achieve a safe and radical resection? a case report and review of the literature. [2023]

6. United States pubmed.ncbi.nlm.nih.gov

Adverse Events of Cabozantinib Plus Nivolumab Versus Ipilimumab Plus Nivolumab. [2023]

7. Egypt pubmed.ncbi.nlm.nih.gov

Efficacy and Safety of Nivolumab for Advanced Renal Cell Carcinoma: A Systematic Review and Meta-Analysis. [2022]

8. United States pubmed.ncbi.nlm.nih.gov

Nivolumab plus Cabozantinib versus Sunitinib for Advanced Renal-Cell Carcinoma. [2022]

9. Australia pubmed.ncbi.nlm.nih.gov

Efficacy and safety of first-line nivolumab plus ipilimumab in patients with metastatic renal cell carcinoma: A multicenter retrospective study. [2021]

10. Switzerland 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. [2022]