A Phase 1/2 First-Time-in-Human, open-label, multicenter, dose escalation and expansion study of the oral DNA Polymerase Theta Inhibitor (POLQi) GSK4524101 and the PARP inhibitor (PARPi) niraparib in adult participants with solid tumors.

The primary objective of Part 1 (Dose Escalation) is to determine the maximum tolerated dose (MTD) and the maximum tolerated dose in combination (MTDc) based on safety, available pharmacokinetic, and available pharmacodynamic profiles observed after oral administration of GSK4524101 as monotherapy and in combination with niraparib. This phase will be conducted in adult participants with advanced or metastatic solid tumors who have exhausted all standard of care treatment options, with preferential enrollment of participants who may potentially benefit based upon the mechanism of action of DNA Polymerase Theta inhibitor (POLQi) or PARP inhibitor (PARPi). Part 1 will also include a food effect cohort. The primary objective of Part 2 (Dose Expansion) is to investigate the preliminary clinical activity of GSK4524101 in combination with niraparib at a dose lower, at, or near (but not above) the MTDc tested in Part 1 and to provide proof-of-concept for the GSK4524101 and niraparib combination. This phase will enroll adult participants with metastatic, germline BRCA-mutated (gBRCAmut), HER2-negative or HER2-low breast cancer who have completed at most 3 lines of prior therapy and are PARPi-naïve.

The secondary objectives include: • Part 1 – Characterize pharmacokinetics or exposure of GSK4364973 after administration of GSK4524101 as monotherapy and in combination with niraparib • Part 1 – Characterize pharmacokinetics or exposure of niraparib when administered in combination with GSK4524101 • Part 1 – Assess the long-term safety and tolerability of GSK4524101 and niraparib combination • Part 2 – Further evaluate the safety of GSK4524101 in combination with niraparib administered in the dose expansion regimen (DER) • Part 2 – Further evaluate the clinical activity of GSK4524101 in combination with niraparib • Part 2 – Characterize pharmacokinetics or exposure of GSK4364973/GSK4524101 in combination with niraparib

This clinical trial enrolled a total of **68 participants** with **neoplasms**, specifically focusing on individuals with advanced or metastatic solid tumors. The study population included both **male and female participants** aged **18 years and older**. Participants were required to have an **Eastern Cooperative Oncology Group (ECOG) performance status** of 0 to 2 and a minimum **life expectancy** of 3 months. The trial was divided into two parts: Part 1 enrolled adults with advanced or metastatic solid tumors who had exhausted all standard of care treatment options, while Part 2 specifically enrolled adults with **metastatic**, **germline BRCA-mutated (gBRCAmut)**, **HER2-negative** or **HER2-low breast cancer** who had completed at most 3 prior lines of therapy and were **PARP inhibitor-naïve**. The study population was classified as patients, and vulnerable populations were included in the trial design.

This Phase 1/2 first-time-in-human, open-label, multicenter study evaluates the safety, tolerability, pharmacokinetics, and preliminary anticancer activity of the oral DNA Polymerase Theta Inhibitor GSK4524101 administered as monotherapy and in combination with the PARP inhibitor niraparib in adult participants with solid tumors. The study is designed as a dose escalation and expansion trial investigating neoplasms. The investigational medicinal product GSK4524101 is administered as a tablet for oral use, while niraparib is provided as film-coated tablets and tablets for oral use. The study is conducted in two distinct parts with different objectives and participant populations.

Part 1 consists of dose escalation aimed at determining the maximum tolerated dose (MTD) of GSK4524101 monotherapy and the maximum tolerated dose in combination (MTDc) with niraparib based on safety, available pharmacokinetic, and pharmacodynamic profiles. This part enrolls adult participants with advanced or metastatic solid tumors who have exhausted all standard of care treatment options. The study preferentially enrolls participants who may potentially benefit based upon the mechanism of action of DNA Polymerase Theta Inhibitor or PARP inhibitor. Part 1 also includes a food effect cohort to evaluate the influence of food intake on drug absorption and metabolism.

Part 2 represents the dose expansion phase and investigates the preliminary clinical activity of GSK4524101 in combination with niraparib at a dose lower, at, or near the MTDc established in Part 1. This part aims to provide proof-of-concept for the combination therapy. Part 2 enrolls adult participants with metastatic, germline BRCA-mutated, HER2-negative or HER2-low breast cancer who have completed at most 3 prior lines of therapy and are PARP inhibitor-naïve. The combination approach utilizes the principle of synthetic lethality to target cancer cells with specific genetic vulnerabilities.

Principal inclusion criteria for the study require participants to be 18 years of age or older with an Eastern Cooperative Oncology Group performance status of 0 to 2 and a life expectancy of a minimum of 3 months. For Part 1, participants must have histologically diagnosed advanced or metastatic solid tumor and have exhausted all standard of care treatment options. For Part 2, participants must have metastatic, germline BRCA-mutated, HER2-negative or HER2-low breast cancer who have completed at most 3 prior lines of therapy.

The primary endpoints for Part 1 include the proportion of participants with dose limiting toxicities during the DLT observation period, the proportion of participants with treatment emergent adverse events and serious adverse events based on severity during the DLT observation period, duration of treatment emergent adverse events and serious adverse events measured in days, percentage of participants who receive all planned doses, and percentage of participants who require dosage interruptions, dose reductions, and drug discontinuations due to adverse reactions during the DLT observation period. The primary endpoint for Part 2 is the confirmed objective response rate.

Secondary endpoints for Part 1 include pharmacokinetic parameters such as area under curve, time to maximum concentration, and half-life of GSK4364973, as well as maximum concentration of GSK4364973 and plasma concentration of niraparib. Additional secondary endpoints assess the number of participants with treatment emergent adverse events and serious adverse events based on severity beyond the DLT observation period and the duration of these events. For Part 2, secondary endpoints include the number of participants with treatment emergent adverse events and serious adverse events based on severity, duration of these events, progression-free survival, duration of response, and minimum concentration of GSK4364973. Both parts evaluate maximum concentration of GSK4364973 and plasma concentration of niraparib as shared secondary endpoints.

The estimated recruitment start date for the study is October 31, 2025, with an estimated end date of June 29, 2027. The duration of participant involvement varies depending on individual response to treatment, tolerability, and disease progression. Participants may be withdrawn from the study due to unacceptable toxicity, disease progression, participant withdrawal of consent, or investigator decision based on safety concerns or protocol violations.

The experimental medication GSK4524101 contains the active substance GSK4524101A and is formulated as a tablet for oral use. This investigational agent functions as a DNA Polymerase Theta inhibitor (POLQi) and is being evaluated in combination with niraparib in adult participants with solid tumors. The study employs a dose escalation approach in Part 1 to determine the maximum tolerated dose (MTD) for GSK4524101 monotherapy and the maximum tolerated combination dose (MTDc) when administered with niraparib. Part 1 includes a food effect cohort to assess the impact of food on drug administration. In Part 2, GSK4524101 will be administered in combination with niraparib at a dose lower, at, or near the MTDc established in Part 1.

Niraparib, containing the active substance niraparib tosilate monohydrate, is utilized as a comparator treatment in this clinical trial. Niraparib is a PARP inhibitor (PARPi) and is available in multiple formulations, including Zejula 100 mg film-coated tablets, which are authorized medicinal products marketed under the authorization number EU/1/17/1235/005 and EU/1/17/1235/004. Additional formulations include tablets with sponsor product code GSK3985771. All niraparib formulations are administered via oral use. The combination of GSK4524101 and niraparib exploits the mechanism of synthetic lethality in participants with advanced or metastatic solid tumors.

Part 1 of the study enrolls adult participants with advanced or metastatic solid tumors who have exhausted all standard of care treatment options, with preferential enrollment of participants who may benefit based on the mechanism of action of POLQi or PARPi. Part 2 focuses on adult participants with metastatic, germline BRCA-mutated (gBRCAmut), HER2-negative or HER2-low breast cancer who have completed at most 3 lines of prior therapy and are PARPi-naïve. The study monitors safety, pharmacokinetic profiles, and pharmacodynamic profiles to guide dose selection and assess preliminary clinical activity of the combination therapy.

Efficacy will be assessed using distinct endpoints for the dose escalation and dose expansion phases of the trial. In Part 1, the primary efficacy endpoint is the proportion of participants with dose limiting toxicities during the dose limiting toxicity observation period, along with the proportion of participants with treatment emergent adverse events and serious adverse events based on severity, the duration of treatment emergent adverse events and serious adverse events measured in days, the percentage of participants who receive all planned doses, and the percentage of participants who require dosage interruptions, dose reductions, and drug discontinuations due to adverse reactions. In Part 2, the primary efficacy endpoint is confirmed objective response rate. Secondary endpoints include pharmacokinetic parameters such as area under curve, time to maximum concentration, half-life, maximum concentration, and minimum concentration of the investigational agent, as well as plasma concentration of niraparib. Additional secondary endpoints in Part 2 include progression-free survival and duration of response. Safety assessments beyond the dose limiting toxicity observation period in Part 1 and throughout Part 2 include the number of participants with treatment emergent adverse events and serious adverse events based on severity and the duration of these events measured in days.