Investigating a new cancer treatment for solid tumors

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)

This study is testing a new cancer treatment that combines a DNA-targeting drug with another medication to see if it helps people with advanced solid tumors.

Quick facts

• Phase: Phase1; Phase2
• Study type: Interventional
• Enrollment: 73 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: GlaxoSmithKline (Industry-sponsored)
• Drugs / interventions: immunotherapy
• Locations: 4 sites (Denver, Colorado and 3 other locations)
• Trial ID: NCT06710847 on ClinicalTrials.gov

What this trial studies

This study evaluates the safety and effectiveness of GSK4418959, a DNA helicase Werner inhibitor, either alone or in combination with a PD-1 inhibitor in patients with advanced solid tumors. Participants will be monitored for changes in tumor size and how the drug is processed in the body over time. The study focuses on patients with specific genetic characteristics that may influence treatment outcomes. It aims to provide insights into the potential benefits of this combination therapy for challenging cancer types.

Who should consider this trial

Good fit: Ideal candidates include individuals with advanced solid tumors that are unresectable, metastatic, or recurrent, and who have specific genetic markers.

Not a fit: Patients with solid tumors that do not have the required genetic characteristics or those who are not seeking further treatment may not benefit from this study.

Why it matters

Potential benefit: If successful, this treatment could offer a new therapeutic option for patients with aggressive solid tumors.

How similar studies have performed: Other studies have shown promise with similar approaches targeting genetic characteristics in solid tumors, suggesting potential for success.

Eligibility 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:

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

Where this trial is running

Denver, Colorado and 3 other locations

• GSK Investigational Site — Denver, Colorado, United States (Recruiting)
• GSK Investigational Site — Chiba, Japan (Recruiting)
• GSK Investigational Site — Tokyo, Japan (Recruiting)
• GSK Investigational Site — Tokyo, Japan (Recruiting)

Study contacts

• Study coordinator: US GSK Clinical Trials Call Center

Conditions Neoplasms, Colorectal; Solid Tumor; Colon Cancer; Rectal Cancer; Endometrial Cancer; GSK4418959; DNA Helicase Werner Inhibitor; PD-1 inhibitor