Phase 1/2 Open‑Label Study of Oral GSK5460025A Monotherapy and Combination Therapy Assessing Safety and Efficacy in dMMR/MSI‑H Tumors, colorectal and endometrial cancer

The primary objective is to determine safety and tolerability, and to identify the recommended dose for expansion (RDE) and/or maximum tolerated dose (MTD) of oral GSK5460025 as monotherapy, as well as to evaluate preliminary anti‑tumor activity in colorectal cancer (CRC) and endometrial cancer (EC) that are Mismatch Repair‑deficient (dMMR) or Microsatellite Instability‑High (MSI‑H); establishing a safe dosing range and early efficacy signals is essential for further development in these molecular subtypes. Secondary objectives include characterizing the drug’s pharmacokinetic profile as monotherapy, further assessing safety and tolerability in the dose‑finding phase, evaluating safety and tolerability at the RDE in CRC and EC, and further investigating anti‑tumor activity in participants with advanced dMMR/MSI‑H CRC and EC.

The trial enrolled 20 adult participants of both sexes, each aged 18 years or older, with an Eastern Cooperative Oncology Group performance status of 0‑2. All subjects had histologically confirmed advanced (unresectable, metastatic or recurrent) solid tumors and were required to have a known dMMR/MSI‑H status or to undergo central testing to determine this biomarker. For the cohort evaluating anti‑tumor activity, participants had a documented diagnosis of Colorectal cancer or endometrial cancer, had received one to three prior lines of systemic anticancer therapy—including at least one line of immune‑checkpoint inhibitor therapy—and possessed at least one measurable lesion per RECIST 1.1. Additional inclusion criteria encompassed a minimum three‑month life expectancy, adequate organ function, and provision of an archival or fresh FFPE tissue sample. The population included patients considered vulnerable, with enrollment limited to those who had exhausted standard‑of‑care treatment options and who intended to receive the investigational therapy as their next treatment.

The study is an open‑label, multicenter, integrated Phase 1/2 trial evaluating oral GSK5460025 as monotherapy and in combination with other anticancer agents in adult participants with dMMR/MSI-H solid tumours. Part 1 employs a dose‑escalation design to identify the maximum tolerated dose or recommended dose for expansion; participants receive escalating oral capsule doses and are observed for dose‑limiting toxicities during a predefined observation period. Part 2 enrolls separate cohorts of patients with advanced colorectal or endometrial cancer who have received 1–3 prior systemic regimens, including an immune‑checkpoint inhibitor, to assess preliminary anti‑tumour activity. The trial sequence includes a screening visit to confirm eligibility and collect archival or fresh tumour tissue, a baseline assessment, and initiation of treatment cycles. Clinic visits occur every 3 weeks for safety evaluation, laboratory tests, ECGs, and pharmacokinetic sampling, with radiographic disease assessment every 8 weeks per RECIST 1.1. Participants remain on study until disease progression, unacceptable toxicity, withdrawal of consent, or study termination, with a final end‑of‑study visit to document outcomes. Expected participant involvement extends from the screening period through multiple treatment cycles, potentially up to 12 months of follow‑up. Early termination criteria include occurrence of dose‑limiting toxicities, treatment‑emergent serious adverse events related to the study drug, or investigator determination that continued therapy is not in the participant’s best interest.

The investigational product, GSK5460025A, is supplied as an oral capsule for use in adult participants with Mismatch Repair-deficient (dMMR) or Microsatellite Instability-High (MSI‑H) solid tumours. The capsule is administered by the oral route. Dosing follows a protocol-defined escalation scheme to identify the recommended dose for expansion (RDE) and/or the maximum tolerated dose (MTD); each dose level is given once daily in continuous 28‑day cycles unless dose adjustments are required for safety reasons.

Non‑experimental therapy may consist of standard‑of‑care anti‑cancer agents selected by the investigator for combination with GSK5460025A, in accordance with current clinical practice for the specific tumour type. These agents are administered according to their approved dosing regimens and may be adjusted or discontinued based on tolerability and efficacy assessments.

Drug administration is recorded in the trial e‑CRF, and participant compliance is monitored through pill counts performed at each study visit, review of dosing diaries, and plasma pharmacokinetic sampling where applicable. Dose modifications or interruptions are guided by predefined toxicity management algorithms.

Efficacy will be evaluated primarily by the Objective Response Rate (ORR), defined as the proportion of participants achieving a confirmed complete response (CR) or partial response (PR) according to RECIST 1.1 criteria as assessed by the investigator. Secondary efficacy assessments include progression‑free survival (PFS), measured from the date of first dose to the first occurrence of disease progression per RECIST 1.1 or death from any cause, and duration of response (DoR), measured from the date of first documented CR or PR to disease progression or death for participants who attain a confirmed response.

Tumor assessments will be performed using imaging studies evaluated by investigators at predefined intervals consistent with standard RECIST 1.1 schedules for phase I/II oncology trials. Plasma concentrations of GSK5460025 will be collected to support pharmacokinetic‑pharmacodynamic correlation with efficacy outcomes.