XL092 + Immuno-Oncology Agents for Solid Tumors

(STELLAR-002 Trial)

Recruiting at 143 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

1274 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial is testing a new drug called XL092 alone and with other cancer drugs in patients with advanced solid tumors. The goal is to see if these treatments can safely stop or slow tumor growth and help the immune system fight cancer more effectively.

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.

What data supports the effectiveness of the drug XL092 in combination with immuno-oncology agents for solid tumors?

The research highlights the effectiveness of combining targeted therapies and immunological agents in treating solid tumors, which has led to significant improvements in survival rates. This suggests that using XL092, a targeted therapy, with immuno-oncology agents could potentially enhance treatment outcomes for solid tumors. ^{1 2 3 4 5}

What safety information is available for XL092 and similar immuno-oncology treatments?

Immuno-oncology treatments, like those involving immune checkpoint inhibitors, can cause immune-related side effects, which are often mild but can include inflammation in various parts of the body. It's important for patients to be monitored for these side effects, even after stopping treatment, as they can occur later. ^{6 7 8 9 10}

What makes the drug XL092 unique for treating solid tumors?

XL092 is unique because it combines with immuno-oncology agents to target solid tumors, potentially enhancing the immune system's ability to fight cancer. This approach is part of a broader trend in cancer treatment that focuses on using the body's immune response to combat tumors, which differs from traditional chemotherapy that directly attacks cancer cells. ^{2 3 6 11 12}

Eligibility Criteria

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

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

Pregnant or lactating females

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

Timeline

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

Treatment Details

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.

Participant Groups

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

Findings from Research

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

References

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

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

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

Safety and Clinical Activity of MEDI0562, a Humanized OX40 Agonist Monoclonal Antibody, in Adult Patients with Advanced Solid Tumors. [2021]

3. Germany pubmed.ncbi.nlm.nih.gov

[Pharmacotherapy of solid tumors. New hopes and frustrations]. [2021]

4. United States 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. [2019]

5. United States 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. [2021]

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

Primer on immuno-oncology and immune response. [2014]

7. Germany pubmed.ncbi.nlm.nih.gov

Cardiac allograft rejection as a complication of PD-1 checkpoint blockade for cancer immunotherapy: a case report. [2022]

8. England pubmed.ncbi.nlm.nih.gov

Real-world data analyses unveiled the immune-related adverse effects of immune checkpoint inhibitors across cancer types. [2023]

9. England pubmed.ncbi.nlm.nih.gov

Safety profile of immune checkpoint inhibitors: An analysis of the Italian spontaneous reporting system database. [2021]

10. United States 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. [2022]

11. England pubmed.ncbi.nlm.nih.gov

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

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

Novel and Expanded Oncology Drug Approvals of 2016-PART 1: New Options in Solid Tumor Management. [2021]