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
Phase 1
Recruiting
- Conditions
- Neoplasms, ColorectalSolid TumorColon CancerRectal CancerEndometrial Cancer
- Interventions
- Biological: PD-1 inhibitor
- Registration Number
- NCT06710847
- Lead Sponsor
- GlaxoSmithKline
- Brief 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.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 73
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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description Part 1: Dose escalation of GSK4418959 monotherapy GSK4418959 Participants will receive GSK4418959 as monotherapy. Part 2: Dose expansion of GSK4418959 monotherapy GSK4418959 Participants will receive GSK4418959 as monotherapy. Part 3: Dose escalation of GSK4418959 plus PD-1 inhibitor GSK4418959 Participants will receive GSK4418959 plus PD-1 inhibitor. Part 3: Dose escalation of GSK4418959 plus PD-1 inhibitor PD-1 inhibitor Participants will receive GSK4418959 plus PD-1 inhibitor.
- Primary Outcome Measures
Name Time Method 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) Up to approximately 26 months 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.
- Secondary Outcome Measures
Name Time Method 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) Up to approximately 42 months 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.
Part 2: Duration of Response (DoR) Up to approximately 42 months 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.
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)
Related Research Topics
Explore scientific publications, clinical data analysis, treatment approaches, and expert-compiled information related to the mechanisms and outcomes of this trial. Click any topic for comprehensive research insights.
How does GSK4418959 inhibit Werner helicase activity in dMMR/MSI-H solid tumors?
What is the comparative efficacy of GSK4418959 plus PD-1 inhibitors vs. standard ICIs in MSI-H cancers?
Which biomarkers predict response to GSK4418959 in mismatch repair-deficient solid tumors?
What are the safety profiles of GSK4418959 combinations in oncology phase 1 trials?
How do WRNi inhibitors like GSK4418959 compare to PARP inhibitors in DNA repair-deficient cancers?
Trial Locations
- Locations (1)
GSK Investigational Site
🇯🇵Tokyo, Japan