GSK4418959A for Mismatch repair-deficient (dMMR) / Microsatellite instability-high (MSI-H) solid tumours | Colorectal cancer | Endometrial cancer

Inclusion criteria

• {"criterion_text":"- Participant is at least 18 years of age.\n- Part 2: Participant has measurable disease (i.e., at least 1 target lesion) during the Screening period per RECIST 1.1, as determined by the investigator.\n- Participant has a histologically diagnosed advanced (unresectable, metastatic or recurrent) solid tumor.\n- Participant has a tumor demonstrating either: -Mismatch repair deficient (dMMR) status as assessed by immunohistochemistry (IHC) for expression of the MMR proteins (MLH1, MSH2, MSH6, PMS2) and where loss of 1 or more of these proteins indicates dMMR; OR -Microsatellite instability-high (MSI-H) phenotype as determined by PCR or by tissue NGS.\n- Participant has an ECOG performance status of 0-2, with no deterioration in the 2 weeks before Cycle 1 Day 1.\n- Participant is expected to have a minimum of 3 months life expectancy.\n- For participants with biopsiable disease and when medically feasible: must provide a fresh biopsy at Screening and must be willing to undergo another on-treatment biopsy.\n- Parts 1 and 3: Participant has histologically diagnosed advanced (unresectable, metastatic or recurrent) solid tumor and has exhausted all standard of care treatment options.\n- Part 2: Participant has histologically diagnosed advanced (unresectable, metastatic or recurrent) CRC or EC.\n- Part 2: Participant has received at least 1 but no more than 3 lines of systemic anticancer therapy for their advanced (unresectable, metastatic or recurrent) disease (i.e., participants are being treated on study in a 2nd to 4th line metastatic setting), including at least one line of ICI therapy."}

Exclusion criteria

• {"criterion_text":"- Participant has not recovered (i.e., to Grade ≤1 or to baseline) from prior anticancer therapy-induced AEs.\n- Participant has an active autoimmune disease that has required systemic treatment in the past 2 years.\n- Part 3: Participant has experienced any of the following with prior immunotherapy: any imAE of Grade ≥3, immune-mediated severe neurologic events of any grade (e.g., myasthenic syndrome/myasthenia gravis, encephalitis, Guillain-Barré Syndrome, or transverse myelitis), exfoliative dermatitis of any grade (Stevens-Johnson Syndrome, toxic epidermal necrolysis, or DRESS syndrome), or myocarditis of any grade. Non-clinically significant laboratory abnormalities are not exclusionary.\n- Part 3: Participant has any history of interstitial lung disease or pneumonitis.\n- Participant has received prior treatment with a WRN inhibitor.\n- Participant is unable to swallow and retain orally administered study treatment.\n- Participant has symptomatic uncontrolled brain or leptomeningeal metastases.\n- Has any impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of study drugs (e.g., severe ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small bowel resection), except for prior gastrectomy.\n- Participant has severe liver fibrosis.\n- Participant has cirrhosis or current unstable liver or biliary disease.\n- Participant has known hypersensitivity to any of the study interventions or any of their excipients.\n- Participant has known WRN syndrome."}

Primary endpoints

• {"endpoint_text":"- Part 1: Incidence of participants with DLTs per dose level in the DLT observation periods.","definition_or_measurement_approach":"DLTs assessed per dose level during the protocol-defined DLT observation periods (as specified for Part 1 dose escalation)."}
• {"endpoint_text":"- Part 1: Incidence of treatment-emergent adverse events (TEAEs) per dose level in the DLT observation periods.","definition_or_measurement_approach":"Treatment-emergent adverse events recorded and tabulated per dose level during the DLT observation periods."}
• {"endpoint_text":"- Part 1: Incidence of dosage interruptions, dose reductions, and drug discontinuations for TEAEs, per dose level in the DLT observation periods.","definition_or_measurement_approach":"Recording of dosage interruptions, dose reductions, and discontinuations attributable to TEAEs per dose level during the DLT observation periods."}
• {"endpoint_text":"- Part 2: Overall response rate, defined as percentage of participants with confirmed complete response (CR) or partial response (PR) per RECIST 1.1 by investigator assessment.","definition_or_measurement_approach":"Overall response rate = % of participants with confirmed CR or PR per RECIST 1.1 assessed by investigator."}
• {"endpoint_text":"- Part 3: Incidence of participants with DLTs per dose level in the DLT observation periods.","definition_or_measurement_approach":"DLTs assessed per dose level during the protocol-defined DLT observation periods for the combination escalation (Part 3)."}
• {"endpoint_text":"- Part 3: Incidence of TEAEs per dose level in the DLT observation periods.","definition_or_measurement_approach":"Treatment-emergent adverse events recorded per dose level during the DLT observation periods for Part 3."}
• {"endpoint_text":"- Part 3: Incidence of dosage interruptions, dose reductions, and drug discontinuations for TEAEs, per dose level in the DLT observation periods.","definition_or_measurement_approach":"Recording of dosage interruptions, dose reductions, and discontinuations attributable to TEAEs per dose level during the DLT observation periods for Part 3."}

Secondary endpoints

• {"endpoint_text":"- Part 1: PK parameters, as available, for GSK4418959 (Key parameters such as AUC, Cmax, Tmax).","definition_or_measurement_approach":"Pharmacokinetic sampling to derive parameters such as AUC, Cmax, Tmax for GSK4418959."}
• {"endpoint_text":"- Part 1: Overall incidence of TEAEs per dose level.","definition_or_measurement_approach":"Tabulation of overall TEAE incidence by dose level."}
• {"endpoint_text":"- Part 1: Overall incidence of dosage interruptions, reductions, and drug discontinuations for TEAEs, per dose level.","definition_or_measurement_approach":"Recording and summarising interruptions/reductions/discontinuations for TEAEs by dose level."}
• {"endpoint_text":"- Part 1: Laboratory abnormalities for key parameters as characterized by type, frequency, severity, and timing.","definition_or_measurement_approach":"Laboratory monitoring with characterization of abnormalities by type, frequency, severity and timing."}
• {"endpoint_text":"- Part 2: Incidence of TEAEs in Part 2.","definition_or_measurement_approach":"Tabulation of TEAEs occurring in Part 2 (dose expansion)."}
• {"endpoint_text":"- Part 2: Overall incidence of dosage interruptions, dose reductions, and drug discontinuations for TEAEs, per dose level.","definition_or_measurement_approach":"Recording of interruptions/reductions/discontinuations for TEAEs in Part 2."}
• {"endpoint_text":"- Part 2: Laboratory abnormalities for key parameters.","definition_or_measurement_approach":"Laboratory monitoring and reporting of key parameter abnormalities in Part 2."}
• {"endpoint_text":"- Part 2: Progression-free survival, defined as time from first dose to progressive disease or death from any cause, whichever is earlier.","definition_or_measurement_approach":"PFS measured as time from first dose to radiographic/clinical progression or death, whichever occurs first."}
• {"endpoint_text":"- Part 2: Duration of Response, defined as time from first documented PR or CR to progressive disease or death from any cause, whichever is earlier for participants who have achieved a confirmed CR or PR.","definition_or_measurement_approach":"Duration of response measured from first documented CR/PR to progression or death."}
• {"endpoint_text":"- Part 2: Plasma PK concentrations, as available, for GSK4418959.","definition_or_measurement_approach":"Plasma PK sampling to determine concentrations of GSK4418959."}
• {"endpoint_text":"- Part 3: PK parameters, as available, for GSK4418959 (Key parameters such as AUC, Cmax, Tmax).","definition_or_measurement_approach":"PK sampling for GSK4418959 when given in combination; derive AUC, Cmax, Tmax as available."}
• {"endpoint_text":"- Part 3: Overall incidence of TEAEs per dose level.","definition_or_measurement_approach":"Tabulation of TEAEs by dose level in Part 3 combination escalation."}
• {"endpoint_text":"- Part 3: Overall incidence of dosage interruptions, reductions, and drug discontinuations for TEAEs, per dose level.","definition_or_measurement_approach":"Recording of interruptions/reductions/discontinuations for TEAEs by dose level in Part 3."}
• {"endpoint_text":"- Part 3: Laboratory abnormalities for key parameters as characterized by type, frequency, severity, and timing.","definition_or_measurement_approach":"Laboratory monitoring with characterization of abnormalities by type, frequency, severity and timing in Part 3."}

Belgium

Earliest CTIS Part Ii Submission Date

09-04-2025

Latest Decision Or Authorization Date

09-02-2026

Processing Time Days

306

Number Of Sites

3

Number Of Participants

9

Spain

Earliest CTIS Part Ii Submission Date

01-07-2025

Latest Decision Or Authorization Date

06-02-2026

Processing Time Days

220

Number Of Sites

4

Number Of Participants

13

Netherlands

Earliest CTIS Part Ii Submission Date

17-06-2025

Latest Decision Or Authorization Date

09-02-2026

Processing Time Days

237

Number Of Sites

3

Number Of Participants

12

Primary sponsor

Full Name

Glaxosmithkline Research & Development Limited

Organisation Type

Pharmaceutical company

Country Of Registered Address

United Kingdom

Contract research organisations

Name

Icon Clinical Research Limited

Responsibilities

Accellacare - Home Health Nursing

Name

Sermes CRO

Responsibilities

patient fee reimbursement

Name

Pharmaceutical Product Development LLC

Name

Eresearchtechnology Inc. (Clario)

Responsibilities

Clario - Cardiac Safety Services

Third parties

• {"country":"United States","full_name":"Neogenomics Inc.","duties_or_roles":"","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"United States","full_name":"Eresearchtechnology Inc.","duties_or_roles":"Clario - Cardiac Safety Services","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Greenphire LLC","duties_or_roles":"Patient Travel and payments","organisation_type":"Non-Pharmaceutical company"}
• {"country":"United States","full_name":"Medable Inc.","duties_or_roles":"","organisation_type":"Non-Pharmaceutical company"}
• {"country":"Ireland","full_name":"Icon Clinical Research Limited","duties_or_roles":"Accellacare - Home Health Nursing","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Charles River Laboratories Inc.","duties_or_roles":"","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Marken LLP","duties_or_roles":"","organisation_type":"Pharmaceutical company"}
• {"country":"Spain","full_name":"Sermes CRO","duties_or_roles":"patient fee reimbursement","organisation_type":"Pharmaceutical company"}
• {"country":"Spain","full_name":"Alcura Health Espana S.A.","duties_or_roles":"medicine product destruction","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Infinity Biologix LLC","duties_or_roles":"","organisation_type":"Pharmaceutical company"}
• {"country":"Germany","full_name":"MARKEN Germany GmbH","duties_or_roles":"Lab Kits Shipment","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Azenta US Inc.","duties_or_roles":"Long Term Storage","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Pharmaceutical Product Development LLC","duties_or_roles":"","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Evidera Inc.","duties_or_roles":"","organisation_type":"Pharmaceutical company"}
• {"country":"Germany","full_name":"Azenta Germany GmbH","duties_or_roles":"Long Term Storage","organisation_type":"Pharmaceutical company"}