XL092 + Nivolumab for Kidney Cancer

(EXACT Trial)

Recruiting at 1 trial location

Overseen By Gabrielle Tiggs

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Karie Runcie

Must be taking: Anti-PD-1/L1

Must not be taking: Complementary medications, Corticosteroids

Disqualifiers: Brain metastases, Active infection, Autoimmune disease, others

Stay on Your Current Meds You can continue your current medications while participating

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

Compensation: Varies

Number of Visits: 92

Duration: Variable (until progression or other criteria)

70 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment approach for individuals with kidney cancer unresponsive to standard anti-PD-1 therapy. Participants will receive either XL092 (a potential new drug) alone or in combination with nivolumab, both targeting cancer growth inhibition. It is intended for those with advanced or metastatic kidney cancer, particularly when previous treatments have failed. Participants should have kidney cancer with a clear-cell component and have previously tried anti-PD-1 therapy without success. As a Phase 2 trial, this research measures the treatment's effectiveness in an initial, smaller group.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, there is a required 2-week washout period for those who have progressed on adjuvant anti-PD-1 therapy before starting the study treatment.

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

A previous study tested the combination of zanzalintinib (XL092) and nivolumab for safety. The results showed that most participants tolerated the combination well. Most side effects were mild or moderate, such as tiredness, nausea, and high blood pressure. Serious side effects, like liver problems, were less common but did occur.

Research has shown that XL092, a drug that blocks signals aiding cancer growth, was also tested on its own. It was generally well-tolerated, with similar mild side effects as when used with nivolumab.

Nivolumab is already an approved drug for some cancers, so its safety profile is well-known. This study focuses on how XL092 and nivolumab work together.

The ongoing Phase 2 trial aims to learn more about how people respond to these treatments, whether used together or separately. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about XL092, especially when used with nivolumab, because it offers a new approach to treating kidney cancer. Unlike standard treatments like tyrosine kinase inhibitors (TKIs) or immune checkpoint inhibitors alone, XL092 is a multi-targeted kinase inhibitor that aims to disrupt cancer cell growth and survival pathways more comprehensively. When combined with nivolumab, an immune checkpoint inhibitor, this treatment might enhance the immune system's ability to attack cancer cells. By potentially offering a dual approach—targeting cancer growth directly and enhancing immune response—these treatments could improve outcomes for patients with kidney cancer.

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

Research has shown that XL092, which participants in this trial may receive in Arm A, has promising effects in shrinking tumors, with a 38% success rate. In Arm B, XL092 is combined with nivolumab, and studies suggest this combination increases the success rate to 63%, allowing patients to go about 18.5 months without the cancer worsening. Nivolumab alone has a 23.1% success rate in treating advanced kidney cancer. These findings suggest that using XL092 with nivolumab might be more effective than using either one alone, offering hope that the combination could better manage kidney cancer symptoms. ^{2 5 6 7 8}

Who Is on the Research Team?

Karie Runcie, MD

Principal Investigator

Columbia University

Are You a Good Fit for This Trial?

Adults over 18 with renal cell carcinoma (a type of kidney cancer) who've seen their cancer progress after standard anti-PD-1/PD-L1 therapy can join. They must have measurable disease, good performance status (able to carry out daily activities), and adequate organ function. Those with unresolved severe side effects from previous treatments or insufficient blood counts are excluded.

Inclusion Criteria

My kidney cancer has spread and shows clear cell features.

Written informed consent and HIPAA authorization for release of personal health information prior to registration. NOTE: HIPAA authorization may be included in the informed consent or obtained separately.

Measurable disease per RECIST 1.1.

Exclusion Criteria

I have had an organ or stem cell transplant from a donor.

I cannot swallow pills.

I do not have serious GI disorders that could lead to holes or abnormal connections.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive XL092 alone or in combination with nivolumab in 28-day cycles until progression, toxicity, or other reasons

Variable (until progression or other criteria)

XL092 daily, nivolumab every 4 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

6 months

What Are the Treatments Tested in This Trial?

Interventions

• Nivolumab
• XL092

Trial Overview

This Phase 2 trial tests XL092 alone or combined with nivolumab in patients whose kidney cancer has worsened despite prior treatment. Participants will be randomly assigned to one of two groups and receive treatment in cycles lasting four weeks until the disease progresses, they experience unacceptable toxicity, or for other reasons.

How Is the Trial Designed?

Group I: Arm B: XL092 and Nivolumab Experimental Treatment 2 Interventions

Study treatment will be given in 28-day (4 week) cycles. Arm B treatment will consist of XL092 60 mg plus nivolumab 480 mg intravenously. XL092 will be taken once daily continuously (Day 1-Day 28) and nivolumab will be administered every 4 weeks (Day 1). Treatment will continue until progression by RECIST 1.1, toxicity, or other reasons as appropriate.

Group II: Arm A: XL092 Experimental Treatment 1 Intervention

Study treatment will be given in 28-day (4 week) cycles. Arm A treatment will consist of XL092 60 mg orally alone and will be taken once daily continuously (Day 1-Day 28). Treatment will continue until progression by RECIST 1.1, toxicity, or other reasons as appropriate.

Who Is Running the Clinical Trial?

Karie Runcie

Lead Sponsor

Trials

1

Recruited

70+

Exelixis

Industry 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

Columbia University

Collaborator

Trials

1,529

Recruited

2,832,000+

Published Research Related to This Trial

Nivolumab, an immune checkpoint inhibitor, appears to be safe for patients with end-stage renal disease (ESRD) and metastatic renal cell carcinoma (mRCC), as none of the three reported cases experienced severe toxicities during treatment.

Among the patients treated with nivolumab, two achieved a partial response, indicating that this therapy can provide clinical benefits for ESRD patients, suggesting that dose adjustments may not be necessary for those on dialysis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Outcomes and Safety of Biweekly and Monthly Nivolumab in Patients with Metastatic Renal Cell Carcinoma and Dialysis: Three Case Reports and Literature Review. Osmán-García, I., Congregado-Ruiz, CB., Lendínez-Cano, G., et al.[2021]

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]

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 a study of 389 metastatic renal cell carcinoma patients with poor prognostic features, nivolumab demonstrated a disease control rate of 53% in those with brain metastasis, 45% in liver metastasis, and 47% in bone metastasis, indicating its efficacy in difficult-to-treat populations.

The safety profile of nivolumab remained consistent with previous studies, with no new safety concerns identified, suggesting it is a safe treatment option for patients with advanced disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Negative prognostic factors and resulting clinical outcome in patients with metastatic renal cell carcinoma included in the Italian nivolumab-expanded access program. Bracarda, S., Galli, L., Maruzzo, M., et al.[2018]

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]

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]

Nivolumab, an immune-checkpoint inhibitor used to treat lung adenocarcinoma, can lead to autoimmune side effects, as demonstrated by a case of acute tubulointerstitial nephritis in a 67-year-old patient after three infusions.

The kidney biopsy revealed specific histological changes, including proliferation of certain immune cells, indicating that nivolumab can trigger significant immune responses that may affect organ function.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tubulointerstitial nephritis as adverse effect of programmed cell death 1 inhibitor, nivolumab, showed distinct histological findings. Uchida, A., Watanabe, M., Nawata, A., et al.[2021]

Citations

1.

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.

2.

ascopubs.org

ascopubs.org/doi/10.1200/JCO.2024.42.16_suppl.TPS4611

Zanzalintinib (XL092) plus nivolumab in non-clear cell ...

In the phase 1 STELLAR-001 study, single-agent zanzalintinib showed promising antitumor activity (38% objective response rate [ORR] and 88% ...

3.

kidneycancer.org

kidneycancer.org/trial/trial-of-xl092-in-combination-with-immunotherapy-in-patients-who-progress-on-adjuvant-therapy-in-clear-cell-rcc/

Trial of XL092 in Combination With Immunotherapy ...

Arm B treatment will consist of XL092 plus nivolumab. XL092 will be taken once daily continuously (Day 1-Day 28) and nivolumab will be administered every 4 ...

4.

clinicaltrials.gov

clinicaltrials.gov/study/NCT06863311

Study Details | NCT06863311 | Trial of Zanzalintinib ...

Study treatment will be given in 28-day (4 week) cycles. Arm A treatment will consist of XL092 60 mg orally alone and will be taken once daily continuously (Day ...

5.

urologytimes.com

urologytimes.com/view/zanzalintinib-plus-nivolumab-shows-safety-efficacy-for-stage-4-rcc

Zanzalintinib plus nivolumab shows safety, efficacy for ...

Zanzalintinib and nivolumab showed a 63% response rate and 18.5-month median PFS in stage 4 RCC. The study included patients with advanced RCC, ...

6.

clinicaltrials.gov

clinicaltrials.gov/study/NCT05176483

NCT05176483 | Study of XL092 in Combination With ...

This is a multicenter Phase 1b, open label, dose-escalation and cohort-expansion study, evaluating the safety, tolerability, PK, preliminary antitumor activity,

7.

pubmed.ncbi.nlm.nih.gov

pubmed.ncbi.nlm.nih.gov/39099411/

Zanzalintinib (XL092): a next-generation tyrosine kinase ...

Zanzalintinib (XL092) is a next-generation anti-VEGFR-related multi-targeted TKI that exhibits immunomodulatory effects.

8.

ir.exelixis.com

ir.exelixis.com/news-releases/news-release-details/exelixis-announces-initiation-phase-1b-trial-evaluating-xl092

Exelixis Announces Initiation of Phase 1b Trial Evaluating ...

XL092 is a next-generation oral tyrosine kinase inhibitor that targets kinases implicated in cancer growth and spread, including VEGF receptors, MET, AXL and ...