A Study to Investigate the Safety, Pharmacokinetics, and Preliminary Effectiveness of GSK4418959 Alone or in Combination With Other Anti-cancer Agents in Participants With Solid Tumors (SYLVER)

A Phase 1/2 First-Time-in-Human, Open-label, Multicenter, Dose Escalation and Expansion Study of the Oral DNA Helicase Werner Inhibitor (WRNi) GSK4418959 Alone or in Combination With Other Anti-cancer Agents in Adult Participants With Mismatch Repair-deficient (dMMR) or Microsatellite Instability-High (MSI-H) Solid Tumors (SYLVER)

Solid tumours are abnormal lumps of tissue that can occur in different parts of the body. The tumours involved in this study have specific genetic characteristics that can make them more aggressive and challenging to treat. The study will test whether GSK4418959 alone or in combination with a PD-1 inhibitor agent can decrease tumor size, is safe, well-tolerated, and how amounts of the study drug decrease in the body over time.

Study Overview

• Status: Active, not recruiting
• Conditions: Rectal Cancer; Solid Tumor; Endometrial Cancer; Colon Cancer; Neoplasms, Colorectal
• Intervention / Treatment: Drug: GSK4418959; Biological: PD-1 inhibitor

• Study Type: Interventional
• Enrollment (Actual): 14
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Australia
  • Victoria
    • Melbourne, Victoria, Australia, 3000
      • GSK Investigational Site
• Belgium
  • Brussels, Belgium, 1200
    • GSK Investigational Site
  • Ghent, Belgium, 9000
    • GSK Investigational Site
  • Leuven, Belgium, 3000
    • GSK Investigational Site
• Japan
  • Chiba, Japan, 277-8577
    • GSK Investigational Site
  • Shizuoka, Japan, 411-8777
    • GSK Investigational Site
  • Tokyo, Japan, 104-0045
    • GSK Investigational Site
  • Tokyo, Japan, 135-8550
    • GSK Investigational Site
• Netherlands
  • Amsterdam, Netherlands, 1066 CX
    • GSK Investigational Site
• South Korea
  • Daegu, South Korea, 41404
    • GSK Investigational Site
  • Gyeonggi-do, South Korea, 10408
    • GSK Investigational Site
  • Seoul, South Korea, 03080
    • GSK Investigational Site
• Spain
  • Barcelona, Spain, 08035
    • GSK Investigational Site
  • Barcelona, Spain, 08023
    • GSK Investigational Site
  • Madrid, Spain, 28040
    • GSK Investigational Site
  • Málaga, Spain, 29010
    • GSK Investigational Site
• United States
  • California
    • Los Angeles, California, United States, 90095
      • GSK Investigational Site
  • Colorado
    • Denver, Colorado, United States, 80218
      • GSK Investigational Site
  • Michigan
    • Detroit, Michigan, United States, 48201
      • GSK Investigational Site
  • New York
    • New York, New York, United States, 10016
      • GSK Investigational Site
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19107
      • GSK Investigational Site
    • Philadelphia, Pennsylvania, United States, 19104
      • GSK Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

Parts 1, 2, and 3 inclusion criteria:

• Has a histologically diagnosed advanced (unresectable, metastatic or recurrent) solid tumor
• Has a known dMMR/MSI-H status as determined by a certified local laboratory at the time of Pre-screening or has an unknown Mismatch repair (MMR)/ Microsatellite Instability (MSI) status at the time of Pre-screening and MMR/MSI status will be determined by central reference laboratory
• Provides an archival or fresh (preferred) formalin fixed, paraffin embedded (FFPE) sample
• Intends to receive GSK4418959 (alone or in combination with PD-1 inhibitor, as determined between Investigator and sponsor) as next line of treatment
• Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
• Is expected to have a minimum of 3 months life expectancy
• Has adequate organ function, as defined in the protocol

Parts 1 and 3 inclusion criteria:

• Has histologically diagnosed advanced (unresectable, metastatic or recurrent) solid tumor and has exhausted all standard of care treatment options

Part 2 inclusion criteria:

• Has histologically diagnosed advanced (unresectable, metastatic or recurrent) Colorectal cancer (CRC) or Endometrial cancer (EC)
• Has received at least 1 but no more than 3 lines of systemic anticancer therapy for their advanced (unresectable, metastatic or recurrent) disease including at least one line of Immune checkpoint inhibitors (ICI) therapy
• 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:

Parts 1, 2, and 3 exclusion criteria:

• Has not recovered (i.e., to Grade ≤1 or to baseline) from prior anticancer therapy-induced AEs
• Has received prior treatment with a WRN inhibitor
• Is unable to swallow and retain orally administered study treatment
• Has symptomatic uncontrolled brain or leptomeningeal metastases
• Has a known additional malignancy that progressed or required active treatment within the last 2 years because reoccurrence of another malignancy would confound interpretation by RECIST 1.1 criteria. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin that has undergone potentially curative therapy, or in situ cancer that is considered to be low risk for progression by the investigator
• Has any impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of study drugs
• Has severe liver fibrosis
• Has cirrhosis or current unstable liver or biliary disease
• Has known hypersensitivity to any of the study interventions or any of their excipients
• Has known WRN syndrome
• Has an active autoimmune disease that has required systemic treatment in the past 2 years

Part 3 exclusion criteria:

• Has experienced any of the following with prior immunotherapy: any immune mediated adverse events (imAE) of Grade ≥3, immune-related severe neurologic events of any grade, exfoliative dermatitis of any grade (Stevens-Johnson Syndrome, toxic epidermal necrolysis, or Drug rash with eosinophilia and systemic signs syndrome [DRESS] syndrome), or myocarditis of any grade. Non-clinically significant laboratory abnormalities are not exclusionary
• Has any history of interstitial lung disease or pneumonitis

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Part 1: Dose escalation of GSK4418959 monotherapy; Participants will receive GSK4418959 as monotherapy.	Drug: GSK4418959; GSK4418959 will be administered.
Experimental: Part 2: Dose expansion of GSK4418959 monotherapy; Participants will receive GSK4418959 as monotherapy.	Drug: GSK4418959; GSK4418959 will be administered.
Experimental: Part 3: Dose escalation of GSK4418959 plus PD-1 inhibitor; Participants will receive GSK4418959 plus PD-1 inhibitor.	Drug: GSK4418959; GSK4418959 will be administered.; Biological: PD-1 inhibitor; PD-1 inhibitor will be administered.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Part 1: Number of participants with dose limiting toxicities (DLTs) during DLT observation period		Up to 21 days
Part 3: Number of participants with dose limiting toxicities (DLTs) during DLT observation period		Up to 21 days
Part 1: Number of participants with treatment emergent adverse events (TEAEs) during DLT observation period		Up to 21 days
Part 3: Number of participants with treatment emergent adverse events (TEAEs) during DLT observation period		Up to 21 days
Part 1: Number of participants with dosage interruptions, dose reductions, and drug discontinuations for TEAEs during DLT observation period		Up to 21 days
Part 3: Number of participants with dosage interruptions, dose reductions, and drug discontinuations for TEAEs during DLT observation period		Up to 21 days
Part 2: Objective Response Rate (ORR)	ORR is defined as percentage of participants with confirmed complete response (CR) or partial response (PR) per Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST 1.1) by investigator assessment.	Up to approximately 26 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Part 1: Area under the concentration-time curve (AUC) for GSK4418959		From first day of dosing for the duration of treatment until end of interventional phase (EOI) (up to approximately 42 months)
Part 1: Maximum concentration (Cmax) for GSK4418959		From first day of dosing for the duration of treatment until end of interventional phase (EOI) (up to approximately 42 months)
Part 1: Time to maximum concentration (Tmax) for GSK4418959		From first day of dosing for the duration of treatment until end of interventional phase (EOI) (up to approximately 42 months)
Part 3: AUC for GSK4418959		From first day of dosing for the duration of treatment until end of interventional phase (EOI) (up to approximately 42 months)
Part 3: Cmax for GSK4418959		From first day of dosing for the duration of treatment until end of interventional phase (EOI) (up to approximately 42 months)
Part 3: Tmax for GSK4418959		From first day of dosing for the duration of treatment until end of interventional phase (EOI) (up to approximately 42 months)
Part 1: Number of participants with TEAEs		Up to approximately 42 months
Part 2: Number of participants with TEAEs		Up to approximately 42 months
Part 3: Number of participants with TEAEs		Up to approximately 42 months
Part 1: Number of participants with dosage interruptions, dose reductions, and drug discontinuations for TEAEs		Up to approximately 42 months
Part 2: Number of participants with dosage interruptions, dose reductions, and drug discontinuations for TEAEs		Up to approximately 42 months
Part 3: Number of participants with dosage interruptions, dose reductions, and drug discontinuations for TEAEs		Up to approximately 42 months
Part 1: Number of participants with clinical laboratory abnormalities		Up to approximately 42 months
Part 2: Number of participants with clinical laboratory abnormalities		Up to approximately 42 months
Part 3: Number of participants with clinical laboratory abnormalities		Up to approximately 42 months
Part 2: Progression-free Survival (PFS)	PFS is defined as time from first dose to progressive disease (as assessed per RECIST 1.1 by Investigator assessment) or death from any cause, whichever is earlier.	Up to approximately 42 months
Part 2: Duration of Response (DoR)	DoR is defined as time from first documented PR or CR to progressive disease (as assessed per RECIST 1.1 by investigator assessment) or death from any cause, whichever is earlier for participants who have achieved a confirmed CR or PR.	Up to approximately 42 months
Part 2: Plasma concentration of GSK4418959		From first day of dosing for the duration of treatment until end of interventional phase (EOI) (up to approximately 42 months)

Collaborators and Investigators

• Sponsor: GlaxoSmithKline
• Collaborators: IDEAYA Biosciences

Study record dates

Study Major Dates

• Study Start (Actual): December 13, 2024
• Primary Completion (Estimated): June 22, 2026
• Study Completion (Estimated): June 22, 2026

Study Registration Dates

• First Submitted: November 26, 2024
• First Submitted That Met QC Criteria: November 26, 2024
• First Posted (Actual): November 29, 2024

Study Record Updates

• Last Update Posted (Actual): February 2, 2026
• Last Update Submitted That Met QC Criteria: January 29, 2026
• Last Verified: January 1, 2026

More Information

Terms related to this study

• Keywords: Colorectal cancer; Rectal cancer; Solid tumors; PD-1 inhibitor; Endometrial cancer; Colon cancer; dMMR; MSI-H; GSK4418959; DNA Helicase Werner Inhibitor (WRNi); Mismatch repair deficient; microsatellite instability high
• Additional Relevant MeSH Terms: Urogenital Diseases; Genital Diseases; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Intestinal Diseases; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Uterine Diseases; Genital Diseases, Female; Colonic Diseases; Genital Neoplasms, Female; Uterine Neoplasms; Rectal Neoplasms; Colorectal Neoplasms; Colonic Neoplasms; Endometrial Neoplasms; Turcot syndrome; Antineoplastic Agents, Immunological; Antineoplastic Agents; Molecular Mechanisms of Pharmacological Action; Pharmacologic Actions; Chemical Actions and Uses; Therapeutic Uses; Immune Checkpoint Inhibitors
• Other Study ID Numbers: 221971; 2024-519721-37-00 (Ctis)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Qualified researchers may request access to anonymized individual patient-level data (IPD) and related study documents of the eligible studies via the Data Sharing Portal. Details on GSK's data sharing criteria can be found at: https://www.gsk.com/en-gb/innovation/trials/data-transparency/
• IPD Sharing Time Frame: Anonymized IPD will be made available within 6 months of publication of primary, key secondary and safety results for studies in product with approved indication(s) or terminated asset(s) across all indications.
• IPD Sharing Access Criteria: Anonymized IPD is shared with researchers whose proposals are approved by an Independent Review Panel and after a Data Sharing Agreement is in place. Access is provided for an initial period of 12 months but an extension may be granted, when justified, for up to 6 months.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes