Evaluation of Safety and Efficacy of XL092 with Nivolumab, Ipilimumab, and Relatlimab in Advanced or Metastatic Solid Tumors

The primary objective of this study is to determine the recommended dose and evaluate the **safety**, tolerability, pharmacokinetics (PK), immunogenicity, and pharmacodynamics of zanzalintinib in combination with the immuno-oncology agents nivolumab (doublet), nivolumab + ipilimumab (triplet), and nivolumab + relatlimab fixed-dose combination (FDC) (triplet) in subjects with advanced cancers. This is clinically relevant as it aims to establish a safe and effective dosing regimen for these combinations, potentially offering new therapeutic options for patients with advanced or metastatic solid tumors.

The clinical trial involves a total of **572 participants** diagnosed with various advanced solid tumors, including **clear cell renal cell carcinoma**, metastatic castration-resistant prostate cancer, urothelial carcinoma, non-clear cell renal cell carcinoma, colorectal cancer, hepatocellular cancer, non-small cell lung cancer, and head and neck squamous cell carcinoma. The study population comprises both male and female subjects aged 18 years and older, with a **Karnofsky Performance Status** of 70% or higher, indicating a requirement for participants to have a relatively stable general health status. Participants were selected based on the presence of unresectable, locally advanced, or metastatic solid tumors for which no life-prolonging therapies exist, or available therapies are intolerable or ineffective. The trial includes individuals from vulnerable populations, and lifestyle considerations such as the use of highly effective contraception methods are mandated for sexually active participants. The selection criteria ensure that participants have adequate organ and marrow function and are capable of understanding and complying with the protocol requirements. The trial does not specify any particular dietary or physical activity requirements for participants.

The clinical trial is designed as a **Phase 1b**, open-label, dose-escalation and cohort-expansion study to evaluate the safety, tolerability, pharmacokinetics, and preliminary antitumor activity of zanzalintinib, both as a monotherapy and in combination with immuno-oncology agents such as **nivolumab**, **ipilimumab**, and **relatlimab**. The study targets subjects with advanced or metastatic solid tumors, including clear cell renal cell carcinoma, metastatic castration-resistant prostate cancer, urothelial carcinoma, non-clear cell renal cell carcinoma, colorectal cancer, hepatocellular cancer, non-small cell lung cancer, and head and neck squamous cell carcinoma. The trial is expected to run until December 31, 2030, with recruitment having commenced on February 1, 2023.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as confirmed solid tumor diagnosis, age, performance status, and organ function. The trial consists of two stages: the Dose-Escalation Stage, which aims to determine the recommended dose and assess safety and pharmacokinetics, and the Expansion Stage, which focuses on evaluating the preliminary efficacy and safety of the treatment regimens. Follow-up visits will be scheduled to monitor adverse events, treatment response, and pharmacokinetic parameters. The end-of-study visit will conclude the participant's involvement, which may last up to 108 weeks, depending on the treatment regimen and response.

Participants may be withdrawn from the study early due to reasons such as disease progression, unacceptable toxicity, withdrawal of consent, or non-compliance with the study protocol. The primary endpoints include the incidence and severity of adverse events and the objective response rate in subjects with measurable disease. Secondary endpoints involve the duration of response, progression-free survival, overall survival, and changes in tumor and blood biomarkers. The study employs a rigorous methodology to ensure the collection of reliable and valid data, contributing to the understanding of the safety and efficacy of the investigational treatments in the specified patient population.

The clinical trial involves the administration of several experimental medications, each with specific pharmaceutical forms, dosages, and routes of administration. The **Relatlimab + Nivolumab Fixed Dose Combination (FDC)** is provided as a **solution for infusion**. This combination is administered intravenously, with a maximum daily dose of 9999.99 mg and a total dose limit of 12000.00 mg over a treatment period of up to 24 weeks. The active substances in this combination are **nivolumab** and **relatlimab**, both originating from protein sources.

Another experimental medication used in the trial is **XL092**, which is a **tablet** form. This medication is taken orally, with a maximum daily dose of 120 mg and a total dose limit of 9999.99 mg over a treatment period of up to 108 weeks. The active substance in XL092 is a chemical compound, specifically N-(4-fluorophenyl)-N-(4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)cyclopropane-1,1-dicarboxamide. XL092 functions as a multi-targeted inhibitor of receptor tyrosine kinases.

**Ipilimumab** is also included in the trial as a **concentrate for solution for infusion**. It is administered intravenously, with a maximum daily dose of 1.00 mg/kg and a total dose limit of 4.00 mg/kg over a treatment period of up to 3 weeks. The active substance, **ipilimumab**, is a protein-based compound.

Additionally, **OPDIVO 10 mg/mL concentrate for solution for infusion** is utilized in the study. This medication is administered intravenously, with a maximum daily dose of 480 mg and a total dose limit of 12000 mg over a treatment period of up to 24 weeks. The active substance in OPDIVO is **nivolumab**, which is also protein-based.

Throughout the trial, participant compliance with the dosing schedules is monitored to ensure adherence to the treatment protocols. The trial aims to evaluate the safety, tolerability, and efficacy of these medications, both individually and in combination, in subjects with unresectable advanced or metastatic solid tumors.

The efficacy of the clinical trial will be assessed through a series of primary and secondary endpoints. In the Dose-Escalation Stage, the primary endpoint will focus on the incidence and severity of adverse events (AEs) and serious adverse events (SAEs), including immune-mediated adverse events (imAEs). For the Expansion Stage, the primary endpoint will be the Objective Response Rate (ORR) in subjects with measurable disease, as assessed by the Investigator per RECIST 1.1. Specific cohorts will have additional primary endpoints, such as the duration of radiographic progression-free survival (PFS) for Cohort 3 (metastatic castration-resistant prostate cancer, mCRPC) determined by the Prostate Working Group 3 (PCWG3) criteria, and the overall survival (OS) rate at 6 months for Cohort 10 (colorectal cancer, CRC).

Secondary endpoints in the Expansion Stage will include the duration of response (DOR) and PFS for subjects with measurable disease, assessed by the Investigator per RECIST 1.1. For Cohort 3, additional secondary endpoints will include the proportion of subjects achieving a greater than 50% decrease in prostate-specific antigen (PSA) from baseline, confirmed by a second consecutive PSA assessment at least 3 weeks later, and changes in bone biomarkers. Other secondary endpoints will involve the ORR, DOR, and PFS for selected cohorts as assessed by a Blinded Independent Radiology Committee (BIRC) per RECIST 1.1, overall survival (OS), and the concentration of study treatments (zanzalintinib, nivolumab, ipilimumab, and relatlimab) in plasma or serum at different timepoints. Additionally, changes in tumor and blood biomarkers and the number and percentage of subjects who develop an anti-drug antibody (ADA) response to nivolumab, ipilimumab, or relatlimab will be evaluated.