A Phase I/II 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)

Study Identifier:
221971
CT.gov Identifier:
NCT06710847
EudraCT Identifier:
N/A
EU Trial (CTIS) Number:
2024-519721-37-00
Study Contact Information:
N/A
Recruitment Complete

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Study Summary

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. To assess safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy of GSK4418959, as monotherapy or in combination with a programmed cell death protein-1 (PD-1) inhibitor. The trial comprises WRNi monotherapy dose escalation (part 1), WRNi monotherapy dose expansion (part 2), and dose escalation of WRNi + PD-1 inhibitor (part 3).

Medical Condition
The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.
  • Bowel (Colorectal)
  • Solid Tumor
  • Endometrial
    • Phase
    The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
    I/II
    Sex
    Female & Male
    Age
    18+ years
    Study Drug
  • Drug: Experimental: Part 1
    • Read More
  • Drug: Drug: GSK4418959
  • Drug: Experimental: Part 2
  • Drug: Experimental: Part 3
  • Drug: Biological: PD-1 inhibitor
    • Study Status
    Indicates the current recruitment status or the expanded access status
    Recruitment Complete

    Requirements information
    Inclusion criteria
    • 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 0-1
    • 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
    • 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

    Clinical Study Information for Healthcare Providers

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    Study Locations

    Location
    Investigator
    Status
    Condition(s) Treated at Site
    Location
    START Barcelona
    Barcelona, Spain, 08023
    Investigator
    Tatiana Hernandez Guerrero
    Status
    Recruitment Complete
    Condition(s) Treated at Site
    Bowel (Colorectal)
    Solid Tumor
    Endometrial