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)

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

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