A Phase 1/2 First-Time-in-Human, open-label, multicenter, dose escalation and expansion study of GSK5458514 PSMA targeting T cell engager alone or in combination with other anti-cancer agents in adult participants with metastatic castration-resistant prostate cancer (mCRPC)

The primary objective of this study is to determine the Maximum Tolerated Dose (MTD) and Maximum Administered Dose (MAD) of GSK5458514, a PSMA-targeting T cell engager, and to evaluate its safety and tolerability in participants with metastatic castration-resistant prostate cancer (mCRPC). Establishing the optimal dosing parameters is clinically essential for defining the therapeutic window and identifying dose-limiting toxicities in this patient population with advanced disease.

The secondary objectives include:

• To assess the pharmacokinetic (PK) profile of GSK5458514 in serum, which is critical for understanding drug exposure, distribution, and elimination kinetics in participants with mCRPC.

• To assess the immunogenicity against GSK5458514, evaluating the potential development of anti-drug antibodies that may impact therapeutic efficacy and safety.

• To evaluate the clinical activity of GSK5458514 in participants with mCRPC, providing preliminary evidence of therapeutic benefit in this advanced malignancy.

This clinical trial enrolled a total of **25 participants** diagnosed with **metastatic castration-resistant prostate cancer** (mCRPC). The study population consisted exclusively of **male participants** aged **18 years or older**. All participants had histologically or cytologically confirmed **adenocarcinoma of the prostate** with metastatic disease documented through radiologic imaging modalities such as PET-CT, CT, MRI, or bone scan. The trial population was selected based on specific disease characteristics, including prior treatment failure with novel anti-androgen receptor therapy and 1-2 taxane-based chemotherapy regimens. Participants were required to have castration-resistant status with serum **testosterone levels below 50 ng/dL** and documented disease progression according to PCWG3 criteria. All participants maintained continuous androgen-deprivation therapy throughout the study and demonstrated an **ECOG performance status** of 1 or less. Adequate organ function was required for enrollment. Male participants agreed to specific contraceptive measures during the study intervention period and for at least 195 days following the last dose, including refraining from sperm donation and using appropriate contraception methods during heterosexual intercourse. Tumor tissue samples, either from newly obtained biopsies or archival sources, were required for biomarker analysis including PSMA expression detection.

This is a Phase 1/2, **first-time-in-human**, **open-label**, **multicenter** study designed to evaluate **GSK5458514**, a **PSMA targeting T cell engager**, administered alone or in combination with other **anti-cancer agents** in adult participants with **metastatic castration-resistant prostate cancer**. The study employs a **dose escalation** and **expansion** design to determine the **maximum tolerated dose** or **maximum administered dose** and to evaluate the **safety** and **tolerability** of the investigational medicinal product. GSK5458514 is formulated as a **powder for solution for infusion** and is administered via **intravenous use**. The primary objectives focus on identifying dose-limiting toxicities during the observation period and assessing the number of participants experiencing **adverse events**, **serious adverse events**, and adverse events leading to dose modifications. Secondary objectives include evaluation of **pharmacokinetic parameters** such as **area under concentration** and **maximum concentration**, assessment of **anti-drug antibodies** development and titers, and measurement of efficacy endpoints including **prostate-specific antigen** decrease from baseline of at least 50 percent and **objective response rate**.

Eligible participants must be male adults aged 18 years or older with histologically or cytologically confirmed **adenocarcinoma of the prostate**. Participants must have **metastatic disease** confirmed by radiologic imaging such as **positron emission tomography**, **computed tomography**, **magnetic resonance imaging**, or bone scan, and must meet **castration-resistant status** as defined by established criteria. Prior treatment requirements include failure of novel **anti-androgen receptor therapy** and treatment failure with one to two **taxane-based chemotherapy** regimens. Participants must demonstrate documented disease progression on their most recent systemic therapy and maintain serum **testosterone** levels below 50 nanograms per deciliter. Additional requirements include **Eastern Cooperative Oncology Group performance status** of one or less, adequate organ function, and provision of tumor tissue for retrospective detection of **prostate-specific membrane antigen** expression and biomarker analysis. Male participants must agree to contraceptive measures and refrain from sperm donation for at least 195 days after the last dose of study intervention.

The trial is estimated to commence recruitment in December 2025 and is expected to conclude in August 2028, representing an overall trial duration of approximately 32 months. Participant involvement duration will vary depending on the assigned treatment cohort and individual response to therapy. The study includes a screening visit to assess eligibility criteria, followed by a step-up treatment period and subsequent treatment cycles. Regular follow-up visits are scheduled to monitor safety parameters, collect pharmacokinetic samples, assess anti-drug antibody development, and evaluate disease response through imaging studies and prostate-specific antigen measurements. An end-of-study visit will be conducted to complete final safety and efficacy assessments. Early termination from the study may occur due to disease progression, unacceptable toxicity, participant withdrawal of consent, dose-limiting toxicities that preclude further treatment, or at the investigator's discretion if continuation is deemed not in the participant's best interest.

The experimental medication under investigation in this clinical trial is **GSK5458514**, a **PSMA targeting T cell engager** designed for the treatment of **metastatic castration-resistant prostate cancer**. GSK5458514 is supplied as a **powder for solution for infusion** and is administered via the **intravenous** route. The active substance is a protein-based compound designated as GSK5458514. This investigational medicinal product is being evaluated in a Phase 1/2 first-time-in-human study with the primary objective of determining the **maximum tolerated dose** (MTD) or **maximum administered dose** (MAD) and assessing the safety and tolerability profile in participants with metastatic castration-resistant prostate cancer. The study follows a dose escalation and expansion design to establish appropriate dosing parameters for this novel therapeutic agent.

The trial protocol indicates that GSK5458514 may be administered alone or in combination with other **anti-cancer agents** as part of the study design. The specific dosing schedules, frequency of administration, and treatment duration will be determined during the dose escalation phase of the study. As this is an **open-label, multicenter** investigation, participant compliance monitoring and dose adjustments will be conducted according to the study protocol requirements and observed safety data throughout the course of treatment.

Efficacy will be assessed through multiple parameters in this clinical trial. The primary efficacy endpoints include the number of participants experiencing dose limiting toxicities during the DLT observation period, the number of participants with adverse events and serious adverse events categorized by severity, and the number of participants with adverse events leading to dose modifications. Secondary efficacy endpoints comprise pharmacokinetic parameters of GSK5458514 following intravenous dose administration, including area under concentration from 0 to t and maximum concentration of GSK5458514, as data permit. Additional secondary endpoints include the number of participants with anti-drug antibodies against GSK5458514 and the titers of anti-drug antibodies against GSK5458514. Clinical efficacy will be further evaluated through prostate-specific antigen decrease from baseline of 50% or greater response rate and objective response rate.