FTIH study to investigate the safety and preliminary efficacy of the DNA-repair inhibitor GSK4418959 alone or in combination with other anti-cancer agents in dMMR/MSI-H solid tumors

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Glaxosmithkline Research & Development Limited

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

6 Aug 2025 → ongoing

Decision date (initial)

2025-07-22

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Pharma R&D

External identifiers

EU CT number

2024-519721-37-00

ClinicalTrials.gov

NCT06710847

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety

"Part 1: Determine the maximum tolerated dose and/or recommended dose for expansion for GSK4418959 as monotherapy; assess safety and tolerability of GSK4418959 as monotherapy within the dose-limiting toxicity (DLT) observation period
Part 2: Evaluate the preliminary anti-tumor activity of GSK4418959 in colorectal cancer and, separately, in endometrial cancer
Part 3: Determine the maximum tolerated dose and/or recommended dose for expansion for GSK4418959 in combination with a PD-1 inhibitor; assess safety and tolerability of GSK4418959 in combination with a PD-1 inhibitor within the DLT observation period"

Secondary objectives 7

1. "Part 1: Characterize the pharmacokinetic (PK) properties of GSK4418959, as monotherapy "
2. Part 1: Further assess the safety and tolerability of GSK4418959 as monotherapy, within and outside of the DLT observation period
3. Part 2: Further evaluate the safety of GSK4418959 administered at the recommended dose for expansion for colorectal and/or endometrial cancer
4. Part 2: Further evaluate the anti-tumor activity of GSK4418959 in colorectal and separately, in endometrial cancer
5. Part 2: Characterize the PK properties of GSK4418959
6. Part 3: Characterize the PK properties of GSK4418959, in combination with a PD-1 inhibitor
7. Part 3: Further assess the safety and tolerability of GSK4418959 in combination with PD-1 inhibitor, within and outside of the DLT observation period

Conditions and MedDRA coding

Neoplasms, Colorectal

Study design 3 periods

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 10

1. "Participant is at least 18 years of age. "
2. Participant has a histologically diagnosed advanced (unresectable, metastatic or recurrent) solid tumor.
3. 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.
4. Participant has an ECOG performance status of 0-2, with no deterioration in the 2 weeks before Cycle 1 Day 1.
5. Participant is expected to have a minimum of 3 months life expectancy.
6. 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.
7. Parts 1 and 3: Participant has histologically diagnosed advanced (unresectable, metastatic or recurrent) solid tumor and has exhausted all standard of care treatment options.
8. Part 2: Participant has histologically diagnosed advanced (unresectable, metastatic or recurrent) CRC or EC.
9. 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.
10. 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.

Exclusion criteria 12

1. "Participant has not recovered (i.e., to Grade ≤1 or to baseline) from prior anticancer therapy-induced AEs. "
2. Participant has received prior treatment with a WRN inhibitor.
3. Participant is unable to swallow and retain orally administered study treatment.
4. Participant has symptomatic uncontrolled brain or leptomeningeal metastases.
5. 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.
6. Participant has severe liver fibrosis.
7. Participant has cirrhosis or current unstable liver or biliary disease.
8. Participant has known hypersensitivity to any of the study interventions or any of their excipients.
9. Participant has known WRN syndrome.
10. Participant has an active autoimmune disease that has required systemic treatment in the past 2 years.
11. "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. "
12. Part 3: Participant has any history of interstitial lung disease or pneumonitis.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 7

1. "Part 1: Incidence of participants with DLTs per dose level in the DLT observation periods. "
2. "Part 1: Incidence of treatment-emergent adverse events (TEAEs) per dose level in the DLT observation periods. "
3. Part 1: Incidence of dosage interruptions, dose reductions, and drug discontinuations for TEAEs, per dose level in the DLT observation periods.
4. 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.
5. "Part 3: Incidence of participants with DLTs per dose level in the DLT observation periods. "
6. "Part 3: Incidence of TEAEs per dose level in the DLT observation periods. "
7. Part 3: Incidence of dosage interruptions, dose reductions, and drug discontinuations for TEAEs, per dose level in the DLT observation periods.

Secondary endpoints 14

1. "Part 1: PK parameters, as available, for GSK4418959 (Key parameters such as AUC, Cmax, Tmax). "
2. "Part 1: Overall incidence of TEAEs per dose level. "
3. "Part 1: Overall incidence of dosage interruptions, reductions, and drug discontinuations for TEAEs, per dose level. "
4. Part 1: Laboratory abnormalities for key parameters as characterized by type, frequency, severity, and timing.
5. "Part 2: Incidence of TEAEs in Part 2. "
6. "Part 2: Overall incidence of dosage interruptions, dose reductions, and drug discontinuations for TEAEs, per dose level. "
7. "Part 2: Laboratory abnormalities for key parameters. "
8. "Part 2: Progression-free survival, defined as time from first dose to progressive disease or death from any cause, whichever is earlier. "
9. 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.
10. Part 2: Plasma PK concentrations, as available, for GSK4418959.
11. "Part 3: PK parameters, as available, for GSK4418959 (Key parameters such as AUC, Cmax, Tmax). "
12. "Part 3: Overall incidence of TEAEs per dose level. "
13. "Part 3: Overall incidence of dosage interruptions, reductions, and drug discontinuations for TEAEs, per dose level. "
14. Part 3: Laboratory abnormalities for key parameters as characterized by type, frequency, severity, and timing.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Glaxosmithkline Research & Development Limited

Sponsor organisation

Glaxosmithkline Research & Development Limited

Address

G S K House, 980 Great West Road 980 Great West Road

City

Brentford

Postcode

TW8 9GS

Country

United Kingdom

Scientific contact point

Organisation

Glaxosmithkline Research & Development Limited

Contact name

EU GSK Clinical Trials Call Center

Public contact point

Organisation

Glaxosmithkline Research & Development Limited

Contact name

EU GSK Clinical Trials Call Center

Third parties 15

Locations

3 EU/EEA countries · 8 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Oversight and notifications

Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77

Urgent safety measures 1 · Art. 54 CTR

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 55 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

4 submissions — initial application plus substantial / non-substantial modifications