Zanzalintinib Combinations for Renal Cell Carcinoma

No longer recruiting at 18 trial locations

Overseen By Backup or International

Age: 18+

Sex: Any

Trial Phase: Phase 1

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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine the appropriate doses and assess the safety and effectiveness of a new treatment combination for individuals with advanced clear cell renal cell carcinoma (ccRCC) or other advanced solid tumors. The trial tests two combinations: one with the drugs zanzalintinib (XL092) and AB521, and another that adds nivolumab (Opdivo) to these two. It seeks participants with advanced or metastatic ccRCC or other solid tumors, regardless of prior cancer treatments. This trial may suit those who have struggled with ccRCC or a similar condition and meet specific health criteria. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new treatment.

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.

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

Research shows that the combination of zanzalintinib and AB521 remains in early testing stages, so limited safety information is available. However, zanzalintinib has been tested with other drugs, such as nivolumab, and has demonstrated manageable safety in other studies. Specifically, the STELLAR-002 study found that patients with advanced kidney cancer tolerated the combination of zanzalintinib and nivolumab well, with manageable side effects.

Nivolumab, part of the treatment in this trial, has FDA approval for other cancers, indicating general safety when used alone or with other treatments.

As this trial is in its early phase, it focuses on determining the right doses and understanding patient tolerance. Safety is a key question the study aims to answer. Participants in such trials receive close monitoring to manage any side effects that may arise. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for renal cell carcinoma (RCC) because they combine innovative approaches that aren't part of the current standard of care, which typically includes drugs like sunitinib or pazopanib. Zanzalintinib, in combination with AB521 and the immunotherapy nivolumab, offers a novel strategy by potentially enhancing the immune response against cancer cells. This combination could target the cancer more effectively by using nivolumab's ability to boost the immune system alongside the unique mechanisms of Zanzalintinib and AB521. These treatments may provide enhanced efficacy or reduced side effects compared to existing therapies, offering new hope for patients facing this challenging condition.

What evidence suggests that this trial's treatments could be effective for renal cell carcinoma?

Research has shown that combining zanzalintinib and AB521 may help treat advanced kidney cancer, known as renal cell carcinoma (RCC). Earlier studies found that this combination can shrink tumors in patients with metastatic kidney cancer, a more serious form of the disease. In this trial, some participants will receive the combination of zanzalintinib and AB521, while others will receive this combination along with nivolumab, a drug that helps the immune system fight cancer. Adding nivolumab has shown early signs of effectiveness against tumors and is considered safe for patients with advanced RCC. These findings offer hope for using these drug combinations to treat advanced RCC. ^{1 3 6 7 8}

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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 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]

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]

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]

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]

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]

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 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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT06191796

NCT06191796 | Study of Zanzalintinib (XL092) + AB521 ... A Phase 1b/2 Dose-finding and Expansion Study Evaluating the Safety and Efficacy of Zanzalintinib (XL092) Combined With Either AB521 or AB521 Plus Nivolumab in ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12509647/

EXACT: a randomized phase II trial of XL092 (zanzalintinib ... The randomized phase III KEYNOTE-564 trial demonstrated that adjuvant pembrolizumab improves disease-free survival and overall survival compared ...

3. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40008409/

a phase III study of zanzalintinib (XL092) plus nivolumab in ... STELLAR-304 is a phase III trial evaluating first-line zanzalintinib plus nivolumab versus sunitinib in advanced nccRCC.

4. ir.exelixis.com ir.exelixis.com/news-releases/news-release-details/exelixis-and-arcus-biosciences-announce-clinical-trial

Exelixis and Arcus Biosciences Announce Clinical Trial ... ... Zanzalintinib in Combination with AB521 in Patients with Advanced Renal Cell Carcinoma ... efficacy data from this stage are expected in 2024.

5. investors.arcusbio.com investors.arcusbio.com/investors-and-media/press-releases/press-release-details/2024/First-Clinical-Data-for-Arcus-Biosciences-HIF-2a-Inhibitor-Casdatifan-Showed-Promising-Clinical-Activity-and-Tumor-Shrinkage-in-Patients-with-Metastatic-Kidney-Cancer/default.aspx

First Clinical Data for Arcus Biosciences' HIF-2a Inhibitor ... If detected in its early stages, the five-year survival rate for RCC is high; for patients with advanced or late-stage metastatic RCC, however, ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT06191796

NCT06191796 | Study of Zanzalintinib (XL092) + AB521 ... A Phase 1b/2 Dose-finding and Expansion Study Evaluating the Safety and Efficacy of Zanzalintinib (XL092) Combined With Either AB521 or AB521 Plus Nivolumab in ...

7. investors.arcusbio.com investors.arcusbio.com/investors-and-media/press-releases/press-release-details/2024/Arcus-Biosciences-Announces-Clinical-Trial-Collaboration-Agreement-to-Evaluate-Casdatifan-in-Combination-with-Volrustomig-in-Renal-Cell-Carcinoma/default.aspx

Press Release Details - Investors & Media - Arcus Biosciences “Renal cell carcinoma is a known CTLA-4-responsive tumor type, and our first-in-human study with volrustomig monotherapy demonstrated ...

8. ucla.clinicaltrials.researcherprofiles.org ucla.clinicaltrials.researcherprofiles.org/kidney-cancer

UCLA Kidney Cancer Clinical Trials for 2025 — Los Angeles This study will compare the efficacy and safety of belzutifan + lenvatinib versus cabozantinib in participants with advanced renal cell ...