XL092 + Immunotherapy for Cancer

(STELLAR-001 Trial)

Not currently recruiting at 99 trial locations

Overseen By Backup or International

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Exelixis

Must not be taking: Kinase inhibitors, Anticancer antibodies

Disqualifiers: Brain metastases, Uncontrolled illness, 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 examines a new cancer treatment called XL092, both alone and in combination with other drugs, to assess its safety and effectiveness against advanced solid tumors. Researchers aim to determine if these treatments can slow or halt tumor growth. Suitable candidates have a type of cancer that cannot be surgically removed and have not responded to previous treatments. As a Phase 1 trial, this research seeks to understand how the treatment works in people, providing participants the opportunity to be among the first to receive it.

Will I have to stop taking my current medications?

The trial requires that you stop taking certain medications before starting the study treatment. Specifically, you must not have taken any small molecule kinase inhibitors within 2 weeks, or anticancer antibodies, systemic chemotherapy, or hormonal anticancer therapy within 4 weeks before the first dose. Additionally, certain medications cannot be used during the trial.

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

Research has shown that XL092, the main treatment in this study, has a manageable safety profile based on previous studies. No unexpected side effects have been reported, indicating that side effects generally align with those anticipated from similar treatments. XL092 is a new oral drug targeting specific proteins involved in cancer growth.

Reports indicate that when combined with avelumab, another cancer treatment, some serious side effects have occurred. Avelumab can cause strong immune reactions in the body, potentially affecting any organ or tissue.

For the combination of XL092 and atezolizumab, studies are still ongoing. While specific safety results for this combination aren't detailed, atezolizumab itself is known to carry risks of serious immune reactions.

In summary, XL092 alone has demonstrated a manageable safety profile, but combining it with avelumab or atezolizumab presents known risks of serious side effects due to immune system reactions. Always consult a healthcare provider to understand the risks and benefits before joining a trial. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about XL092 because it represents a new approach to cancer treatment. Unlike standard care options that often target cancer cells directly, XL092 is a small molecule inhibitor that works by blocking specific pathways that tumors use to grow and spread. This targeted mechanism of action has the potential to be more precise and may offer effectiveness with potentially fewer side effects. Additionally, when combined with immunotherapies like Avelumab and Atezolizumab, XL092 could enhance the immune system's ability to fight cancer, offering a promising new strategy in the fight against cancers such as renal cell carcinoma, breast cancer, prostate cancer, and colorectal cancer.

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

Research has shown that XL092, a new oral medication, targets key proteins that aid cancer growth and spread. In this trial, some participants will receive XL092 alone, which early studies have shown to stop tumor growth. Others will receive XL092 with atezolizumab, a drug that helps the immune system fight cancer and has initially improved outcomes for certain cancers. Atezolizumab is already approved for some cancers, adding confidence in its use. Additionally, some participants will receive XL092 with avelumab, another drug that boosts the immune system and has shown activity against tumors, especially in advanced breast cancer. These treatments aim to halt cancer cell growth and spread while strengthening the body’s natural defenses. ^{5 6 7 8 9}

Are You a Good Fit for This Trial?

This trial is for adults with advanced solid tumors that are inoperable or metastatic, and who have tried other treatments without success. They must be mostly recovered from previous treatment side effects, not pregnant, able to use contraception, and have good organ function. People with certain cancers like colorectal cancer must meet specific genetic criteria.

Inclusion Criteria

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

I am not pregnant and can become pregnant.

My colon or rectum cancer is advanced, cannot be surgically removed, and lacks certain genetic mutations.

Exclusion Criteria

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

I have previously been treated with XL092, PD-L1/PD-1 inhibitors, regorafenib, or TAS-102 depending on my trial cohort.

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

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose-Escalation

Subjects will accrue in cohorts to determine the maximum tolerated dose (MTD) and/or recommended dose (RD) for XL092 alone and in combination with immune checkpoint inhibitors (ICIs)

Up to 24 months

Cohort-Expansion

The MTD or recommended dose from the dose-escalation stage is further explored in specific cancer types to evaluate preliminary efficacy

Up to 24 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 36 months

What Are the Treatments Tested in This Trial?

Interventions

• Atezolizumab
• Avelumab
• XL092

Trial Overview The study tests XL092 alone or combined with Atezolizumab or Avelumab in patients with various solid tumors. It's an early-phase trial to check safety, how the body processes the drugs (pharmacokinetics), their effect on tumor markers, and initial effectiveness against the cancer.

How Is the Trial Designed?

Group I: XL092 Single-Agent Expansion Cohorts Experimental Treatment 1 Intervention

The MTD or recommended dose from the dose-escalation stage may be further explored in clear cell renal cell carcinoma (ccRCC), non-clear cell renal cell carcinoma (nccRCC), hormone receptor-positive breast cancer (HR+ BC), and metastatic castration-resistant prostate cancer (mCRPC).

Group II: XL092 Single-Agent Dose-Escalation Cohorts Experimental Treatment 1 Intervention

Subjects will accrue in cohorts of 3-6 subjects in a standard "3 plus 3" design.

Group III: XL092 + Avelumab Dose-Escalation Cohorts Experimental Treatment 2 Interventions

Subjects will accrue in cohorts of 2-6 subjects in a "rolling 6" design.

Group IV: XL092 + Atezolizumab Expansion Cohorts Experimental Treatment 2 Interventions

The MTD or recommended dose from the dose-escalation stage may be further explored in non-clear cell renal cell carcinoma (nccRCC), hormone receptor-positive breast cancer (HR+ BC), metastatic castration-resistant prostate cancer (mCRPC), and colorectal cancer (CRC).

Group V: XL092 + Atezolizumab Dose-Escalation Cohorts Experimental Treatment 2 Interventions

Subjects will accrue in cohorts of 2-6 subjects in a "rolling 6" design.

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

Published Research Related to This Trial

In a study analyzing nationwide insurance claims data from 92,858 patients over 8 years, it was found that patients receiving immune checkpoint inhibitors had a 1.50-4.00 times higher risk of developing immune-related adverse events (irAEs) compared to those receiving chemotherapy or targeted therapy.

Among the immunotherapy agents, nivolumab was associated with a higher risk of irAEs than pembrolizumab, highlighting the importance of monitoring these adverse effects in cancer patients undergoing immunotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-world data analyses unveiled the immune-related adverse effects of immune checkpoint inhibitors across cancer types. Wang, F., Yang, S., Palmer, N., et al.[2023]

In a study of 1535 patients receiving high-dose interleukin-2 (IL-2) therapy, those who experienced immune-related adverse events (irAEs) had significantly better tumor control (71% vs. 56%) and overall survival, particularly in metastatic melanoma (median 48 months vs. 18 months) and metastatic renal cell cancer (median 60 months vs. 40 months).

The majority of irAEs were related to IL-2 therapy, primarily manifesting as vitiligo and thyroid dysfunction, indicating that while these adverse events are concerning, they may also signal a beneficial immune response that enhances treatment efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Improved survival and tumor control with Interleukin-2 is associated with the development of immune-related adverse events: data from the PROCLAIMSM registry. Curti, B., Daniels, GA., McDermott, DF., et al.[2018]

Harnessing the immune system for cancer treatment has significantly improved patient outcomes, leading to extended life and even cures, but it can also trigger serious side effects like cytokine release syndrome and neurotoxicity.

The article reviews the biological mechanisms behind these immune-mediated adverse effects and discusses industry strategies using laboratory models to better assess safety risks in immune-oncology treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Current nonclinical approaches for immune assessments of immuno-oncology biotherapeutics. Grimaldi, C., Ibraghimov, A., Kiessling, A., et al.[2023]

Recent cancer treatments, including monoclonal antibodies and kinase inhibitors, have been developed to specifically target cancer pathways, showing promise in improving cancer control.

However, these therapies are associated with significant gastrointestinal and hepatic toxic effects, such as diarrhea and liver damage, which can lead to treatment discontinuation and reduced effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Drug insight: gastrointestinal and hepatic adverse effects of molecular-targeted agents in cancer therapy. Loriot, Y., Perlemuter, G., Malka, D., et al.[2016]

The first-in-human study of MK-4830, a novel IgG4 monoclonal antibody targeting the ILT4 receptor, showed it was well tolerated with no dose-limiting toxicities among 84 patients with advanced solid tumors.

In combination with pembrolizumab, MK-4830 demonstrated promising antitumor activity, with 11 out of 34 patients achieving objective responses, including some who had previously progressed on other therapies, suggesting enhanced effectiveness in certain tumor microenvironments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

First-in-Class Anti-immunoglobulin-like Transcript 4 Myeloid-Specific Antibody MK-4830 Abrogates a PD-1 Resistance Mechanism in Patients with Advanced Solid Tumors. Siu, LL., Wang, D., Hilton, J., et al.[2023]

Anti-CTLA4 and anti-PD1/PD-L1 immunotherapies represent a significant shift in cancer treatment by enhancing the immune system's ability to fight tumors rather than directly targeting the tumor cells themselves.

These immunotherapies can lead to unique immune-related adverse events due to the activation of the immune system against normal tissues, necessitating changes in clinical management to address potential autoimmune reactions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Management of adverse events associated with cancer immunotherapy]. Champiat, S., Michot, JM., Lambotte, O.[2019]

Citations

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

EXACT: a randomized phase II trial of XL092 (zanzalintinib ... The primary endpoint is overall response rate at 6 months as per investigator assessed RECIST 1.1. Secondary endpoints include progression- free ...

2. urotoday.com urotoday.com/recent-abstracts/urologic-oncology/renal-cancer/158598-stellar-304-a-phase-iii-study-of-zanzalintinib-xl092-plus-nivolumab-in-advanced-non-clear-cell-renal-cell-carcinoma.html?page=6

STELLAR-304: a phase III study of zanzalintinib (XL092) plus ... Zanzalintinib may also improve how well the body responds to another type of cancer drug called immune checkpoint inhibitor (ICI), which works by helping the ...

3. ascopubs.org ascopubs.org/doi/10.1200/JCO.2025.43.5_suppl.TPS285

PRO-XL: A phase II study of zanzalintinib (XL092) in ... Prior studies have demonstrated a significant VEGF expression in LNCaP tumors and locally recurrent prostate cancer after radiotherapy. Also ...

4. 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 ...

5. annalsofoncology.org annalsofoncology.org/article/S0923-7534(22)02460-7/fulltext

481P A phase I first-in-human study of XL092 in patients ... As of 2 Mar 2022, 73 pts (47 SA and 26 Combo) received study treatment. Median age was 61y for SA and 64y for Combo and 62% and 58% pts had an ECOG score of 1.

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): a next-generation tyrosine kinase inhibitor-comprehensive review of early safety & efficacy data. Expert Opin Investig ...

8. ascopubs.org ascopubs.org/doi/10.1200/JCO.2022.40.6_suppl.TPS401

A phase 1 first-in-human study of XL092 administered ... XL092 as a single-agent and in combination with an anti-PD-1 antibody showed antitumor activity in xenograft tumor models (Hsu et al. 2020).

9. 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 ... The objective of the study is to evaluate the safety, tolerability and efficacy of XL092, Exelixis' novel next-generation tyrosine kinase inhibitor (TKI), in ...