XL092 + Immuno-Oncology Agents for Solid Tumors

(STELLAR-002 Trial)

Not currently recruiting at 154 trial locations

Overseen By Exelixis Clinical Trials

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Exelixis

Must not be taking: Anticoagulants, Complementary medicines

Disqualifiers: Brain metastases, Uncontrolled illness, Pregnancy, 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 tests a new treatment called XL092, both alone and with other drugs, to assess its safety and effectiveness for people with various advanced solid tumors. The researchers aim to determine the right dose and evaluate any potential benefits against tumors. They seek participants with solid tumors that cannot be surgically removed or have spread, and for whom other treatments have failed or are no longer effective. Those with conditions such as kidney, prostate, bladder, liver, lung, colon, or head and neck cancer that meet these criteria might find this trial suitable. As a Phase 1 trial, this research focuses on understanding how the treatment works in people, and participants could be among the first to receive this new therapy.

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

The trial protocol does not specify if you must stop taking your current medications. However, certain medications like small molecule kinase inhibitors, anticancer antibodies, and some complementary medicines must be stopped 1-4 weeks before starting the trial treatment, depending on the specific cohort.

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

In previous studies, zanzalintinib (also known as XL092) combined with nivolumab showed promising safety results. Reports indicate that a 100-mg dose of zanzalintinib was well-tolerated when used with nivolumab, with or without relatlimab. Most patients handled the treatment well, experiencing few serious side effects. Some mild to moderate side effects occurred but were generally manageable.

When combined with nivolumab and ipilimumab, the safety remained acceptable, and early data supports further research into these combinations. The combination of zanzalintinib with nivolumab and relatlimab also demonstrated acceptable tolerability, with a low rate of severe side effects.

As a single treatment, zanzalintinib has been evaluated for safety, showing promising results in early studies. It has been tested in various solid tumors, and the data suggest it is generally well-tolerated by patients.

These findings suggest that zanzalintinib, both alone and in combinations, has been safe for use in humans so far. However, since this is a Phase 1 trial, the main goal is to further evaluate safety and tolerability in a larger group of patients. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about XL092, also known as Zanzalintinib, because it offers a fresh approach to tackling solid tumors by combining with immuno-oncology agents like Nivolumab, Ipilimumab, and Relatlimab. Unlike standard treatments that might target tumor cells directly, XL092 works by potentially enhancing the immune system's ability to recognize and destroy cancer cells, thanks to its unique combination with these immune checkpoint inhibitors. This combination could lead to more effective and durable responses compared to existing therapies. Additionally, the use of dose-escalation and expansion cohorts allows researchers to tailor the treatment to specific tumor types, optimizing its effectiveness. This innovative approach could represent a significant advancement in cancer treatment, offering hope for better outcomes.

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

Research has shown that Zanzalintinib, especially when combined with other treatments, holds promise for treating various solid tumors. In this trial, participants may receive Zanzalintinib with nivolumab. Studies have reported a 63% rate of tumor shrinkage and a 90% rate of tumor stabilization, indicating that many patients experienced tumor reduction or halted growth. Another arm of this trial will explore Zanzalintinib with nivolumab and relatlimab, which early studies indicate has strong tumor-fighting effects. These findings suggest that combinations with Zanzalintinib could effectively treat advanced solid tumors. ^{1 3 6 7 8}

Are You a Good Fit for This Trial?

This trial is for adults with various advanced solid tumors, including specific types of lung, kidney, liver, prostate, bladder and colorectal cancers. Participants must have a certain level of physical fitness (KPS ≥ 70%), adequate organ function, agree to use contraception if fertile, and not be pregnant. They should not have received certain recent treatments or have other active cancers (except some localized ones).

Inclusion Criteria

My organs and bone marrow are working well.

I can provide samples of my tumor, either from previous tests or new ones if safe.

My cancer is advanced and cannot be removed by surgery.

Exclusion Criteria

Pregnant or lactating females

I haven't taken any kinase inhibitor medication in the last 2 weeks.

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

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose-Escalation

Participants receive Zanzalintinib alone or in combination with immuno-oncology agents to determine the recommended dose

12-24 weeks

Expansion

The safety and efficacy of Zanzalintinib as monotherapy and in combination therapy are evaluated in tumor-specific cohorts

up to 24 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

6 months

What Are the Treatments Tested in This Trial?

Interventions

• XL092

Trial Overview The study tests XL092 alone or combined with immune therapies: nivolumab; nivolumab plus ipilimumab; or nivolumab plus relatlimab. It's in Phase 1b to check safety and how the body processes these drugs while also looking at early signs of their effectiveness against tumors.

How Is the Trial Designed?

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

Group II: Zanzalintinib + Nivolumab Expansion Cohorts Experimental Treatment 2 Interventions

The recommended dose from the dose-escalation stage may be further explored in tumor-specific cohorts.

Group III: Zanzalintinib + Nivolumab Dose-Escalation Cohorts Experimental Treatment 2 Interventions

Approximately 12 subjects will accrue across 1-2 dose levels of Zanzalintinib following the "rolling 6" design.

Group IV: Zanzalintinib + Nivolumab + Relatlimab Expansion Cohorts Experimental Treatment 2 Interventions

The recommended dose from the dose-escalation stage may be further explored in tumor-specific cohorts.

Group V: Zanzalintinib + Nivolumab + Relatlimab Dose-Escalation Cohorts Experimental Treatment 2 Interventions

Approximately 12 subjects will accrue across 1-2 dose levels of Zanzalintinib following the "rolling 6" design.

Group VI: Zanzalintinib + Nivolumab + Ipilimumab Expansion Cohorts Experimental Treatment 3 Interventions

The recommended dose from the dose-escalation stage may be further explored in tumor-specific cohorts.

Group VII: Zanzalintinib + Nivolumab + Ipilimumab Dose-Escalation Cohorts Experimental Treatment 3 Interventions

Approximately 12 subjects will accrue across 1-2 dose levels of Zanzalintinib following the "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]

Anti-CTLA-4 therapy (ipilimumab) is associated with a significantly higher risk of severe colitis compared to anti-PD-1 therapies (nivolumab and pembrolizumab), with a three-fold increase in adverse event reports related to colitis.

The study utilized a novel data analysis platform to explore the molecular mechanisms behind these adverse reactions, but found no significant evidence that the increased colitis rates were due to greater T-cell activation from anti-CTLA-4 therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Application of a patient-centered reverse translational systems-based approach to understand mechanisms of an adverse drug reaction of immune checkpoint inhibitors. Kim, S., Lahu, G., Vakilynejad, M., et al.[2022]

Targeted and immunological therapies have significantly improved survival rates in patients with solid tumors, demonstrating the effectiveness of treatments that focus on specific genetic and immunological changes in tumors.

Current clinical trials are exploring the optimal timing and sequencing of these therapies, which include various approved agents for cancers like prostate, breast, lung, and melanoma, indicating a shift towards more personalized cancer treatment strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Pharmacotherapy of solid tumors. New hopes and frustrations]. Grünwald, V., Rickmann, M.[2021]

In a patient with cutaneous squamous cell cancer and a cardiac allograft, PD-1 antibody therapy led to acute cellular rejection characterized by a high presence of activated CD8+ T cells, indicating a unique toxicity associated with immunotherapy in transplant recipients.

High-intensity immunosuppression successfully reversed the graft rejection, allowing the patient to maintain cardiac function and survive for 7 months after stopping the PD-1 inhibitor nivolumab, suggesting that while immune checkpoint inhibitors can be harmful in allograft patients, effective management strategies exist.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cardiac allograft rejection as a complication of PD-1 checkpoint blockade for cancer immunotherapy: a case report. Owonikoko, TK., Kumar, M., Yang, S., et al.[2022]

Recent advancements in antibody therapies, such as monoclonal antibodies and bispecific T cell engagers, have made cancer treatments more effective while reducing toxicity, enhancing the safety profile of these therapies.

The discovery of immune checkpoints like PD1 and PD-L1 has transformed cancer immunotherapy, allowing for the development of immune checkpoint inhibitors that can effectively treat previously hard-to-treat cancers, such as stage IV lung cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CAR-T "the living drugs", immune checkpoint inhibitors, and precision medicine: a new era of cancer therapy. Liu, D.[2023]

Immunotherapies like sipuleucel-T and ipilimumab enhance the body's own immune response against tumors, leading to significant long-term survival benefits for patients with cancer.

While these treatments can cause immune-related adverse events, which are generally low grade, guidelines for early recognition and management with corticosteroids are crucial for patient safety and ongoing care.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Primer on immuno-oncology and immune response. Kannan, R., Madden, K., Andrews, S.[2014]

A review of 2217 adverse drug reaction reports related to immune checkpoint inhibitors (ICIs) from 2011 to 2018 revealed that these drugs, particularly nivolumab, are associated with a higher frequency of serious immune-related adverse events, including gastrointestinal and respiratory disorders.

Emerging safety signals, such as ischaemic heart disease and cardiac failure, were identified, indicating the need for further investigation into the long-term safety profile of ICIs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety profile of immune checkpoint inhibitors: An analysis of the Italian spontaneous reporting system database. Cutroneo, PM., Isgrò, V., Ientile, V., et al.[2021]

Mapatumumab, a monoclonal antibody targeting TRAIL-R1, was found to be well-tolerated at doses up to 20 mg/kg when combined with standard chemotherapy drugs paclitaxel and carboplatin in a phase I study involving 27 patients.

The study showed preliminary antitumor activity, with 19% of patients achieving a confirmed partial response and 44% having stable disease, indicating potential clinical benefits of this combination therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Mapatumumab, an antibody targeting TRAIL-R1, in combination with paclitaxel and carboplatin in patients with advanced solid malignancies: results of a phase I and pharmacokinetic study. Leong, S., Cohen, RB., Gustafson, DL., et al.[2019]

MEDI0562, an agonistic antibody targeting the OX40 costimulatory molecule, was safely administered to 55 patients with advanced solid tumors, showing a tolerable safety profile with treatment-related adverse events occurring in 67% of patients, primarily fatigue and infusion reactions.

The treatment demonstrated some antitumor activity, with 44% of patients achieving stable disease and two patients showing partial responses, alongside evidence of enhanced T-cell proliferation, indicating potential effectiveness in boosting immune responses against tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and Clinical Activity of MEDI0562, a Humanized OX40 Agonist Monoclonal Antibody, in Adult Patients with Advanced Solid Tumors. Glisson, BS., Leidner, RS., Ferris, RL., et al.[2021]

In 2016, the FDA approved three new drugs for solid tumors: olaratumab for soft-tissue sarcoma, atezolizumab for bladder cancer, and rucaparib for ovarian cancer, highlighting advancements in targeted therapies and immunotherapies.

The year also saw the expansion of previously approved drugs into 11 new patient populations, emphasizing the need for oncologists to understand the mechanisms and potential toxicities of both new and existing treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Novel and Expanded Oncology Drug Approvals of 2016-PART 1: New Options in Solid Tumor Management. Knepper, TC., Saller, J., Walko, CM.[2021]

In a study of 107 patients with NSCLC and specific genetic mutations (BRAF, HER2, MET, RET), immune-checkpoint inhibitors (ICIs) showed a median overall survival of 16.2 months, indicating their potential effectiveness in this population.

Response rates to ICIs varied by mutation type, with the highest response observed in RET-altered NSCLC (38%), and patients with positive PD-L1 status had better progression-free survival and overall survival compared to those who were PD-L1 negative.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and Safety of Anti-PD-1 Immunotherapy in Patients With Advanced NSCLC With BRAF, HER2, or MET Mutations or RET Translocation: GFPC 01-2018. Guisier, F., Dubos-Arvis, C., Viñas, F., et al.[2021]

The combination of lexatumumab, an agonistic antibody targeting TRAIL-R2, with cisplatin showed synergistic cytotoxic effects against human solid cancer cells, enhancing apoptosis and overcoming resistance in certain cancer types.

Cisplatin treatment increased TRAIL-R2 expression and significantly amplified caspase activation, particularly caspase-8, suggesting that this combination therapy could be an effective strategy for treating solid tumors resistant to conventional chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Enhancement of lexatumumab-induced apoptosis in human solid cancer cells by Cisplatin in caspase-dependent manner. Wu, XX., Kakehi, Y.[2017]

Citations

1. ir.exelixis.com ir.exelixis.com/news-releases/news-release-details/exelixis-announces-detailed-results-phase-3-stellar-303-pivotal

Exelixis Announces Detailed Results from Phase 3 STELLAR ... Zanzalintinib in combination with atezolizumab improved median overall survival to 10.9 months versus 9.4 months with regorafenib, and significantly reduced ...

2. ascopubs.org ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.3101

Zanzalintinib (zanza) + nivolumab (nivo) ± relatlimab (rela) ... Results: Among 19 pts in the zanza 100 mg + nivo cohort, the most common tumor types were prostate cancer (26%) and colorectal cancer (26%).

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11916370/

STELLAR-304: a phase III study of zanzalintinib (XL092) plus ... In a phase Ib study in advanced solid tumors, cabozantinib plus atezolizumab (a PD-L1 inhibitor) led to an ORR of 31% (80% CI: 20–44) and median PFS of 9.5 (95% ...

4. targetedonc.com targetedonc.com/view/zanzalintinib-atezolizumab-improves-crc-survival-expands-tki-s-role-in-solid-tumors

Zanzalintinib/Atezolizumab Improves CRC Survival ... New trial results reveal zanzalintinib and atezolizumab significantly enhance survival in metastatic colorectal cancer, marking a breakthrough ...

5. 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,

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 ...

7. clinicaltrials.gov clinicaltrials.gov/study/NCT06191796

NCT06191796 | Study of Zanzalintinib (XL092) + AB521 ... 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 ...

8. clinicaltrials.eu clinicaltrials.eu/trial/study-on-the-safety-and-effects-of-xl092-with-nivolumab-ipilimumab-and-relatlimab-for-patients-with-advanced-solid-tumors/

Study on the Safety and Effects of XL092 with Nivolumab ... This clinical trial investigates the safety and effects of XL092, Nivolumab, Ipilimumab, and Relatlimab in treating various advanced solid tumors, ...