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Trial details imported from ClinicalTrials.gov
For full trial details, please see the original record at
https://clinicaltrials.gov/study/NCT06710847
Registration number
NCT06710847
Ethics application status
Date submitted
26/11/2024
Date registered
29/11/2024
Date last updated
6/08/2025
Titles & IDs
Public title
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
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Scientific title
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)
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Secondary ID [1]
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221971
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Universal Trial Number (UTN)
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Trial acronym
SYLVER
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Linked study record
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Health condition
Health condition(s) or problem(s) studied:
Neoplasms, Colorectal
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Solid Tumor
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Colon Cancer
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Rectal Cancer
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Endometrial Cancer
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Condition category
Condition code
Cancer
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Bowel - Back passage (rectum) or large bowel (colon)
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Cancer
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Womb (Uterine or endometrial cancer)
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Intervention/exposure
Study type
Interventional
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Description of intervention(s) / exposure
Treatment: Drugs - GSK4418959
Treatment: Other - PD-1 inhibitor
Experimental: Part 1: Dose escalation of GSK4418959 monotherapy - Participants will receive GSK4418959 as monotherapy.
Experimental: Part 2: Dose expansion of GSK4418959 monotherapy - Participants will receive GSK4418959 as monotherapy.
Experimental: Part 3: Dose escalation of GSK4418959 plus PD-1 inhibitor - Participants will receive GSK4418959 plus PD-1 inhibitor.
Treatment: Drugs: GSK4418959
GSK4418959 will be administered.
Treatment: Other: PD-1 inhibitor
PD-1 inhibitor will be administered.
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Intervention code [1]
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Treatment: Drugs
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Intervention code [2]
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Treatment: Other
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Comparator / control treatment
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Control group
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Outcomes
Primary outcome [1]
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Part 1: Number of participants with dose limiting toxicities (DLTs) during DLT observation period
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Assessment method [1]
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Timepoint [1]
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Up to 21 days
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Primary outcome [2]
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Part 3: Number of participants with dose limiting toxicities (DLTs) during DLT observation period
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Assessment method [2]
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Timepoint [2]
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Up to 21 days
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Primary outcome [3]
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Part 1: Number of participants with treatment emergent adverse events (TEAEs) during DLT observation period
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Assessment method [3]
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Timepoint [3]
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Up to 21 days
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Primary outcome [4]
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Part 3: Number of participants with treatment emergent adverse events (TEAEs) during DLT observation period
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Assessment method [4]
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Timepoint [4]
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Up to 21 days
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Primary outcome [5]
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Part 1: Number of participants with dosage interruptions, dose reductions, and drug discontinuations for TEAEs during DLT observation period
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Assessment method [5]
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Timepoint [5]
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Up to 21 days
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Primary outcome [6]
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Part 3: Number of participants with dosage interruptions, dose reductions, and drug discontinuations for TEAEs during DLT observation period
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Assessment method [6]
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Timepoint [6]
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Up to 21 days
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Primary outcome [7]
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Part 2: Objective Response Rate (ORR)
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Assessment method [7]
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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.
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Timepoint [7]
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Up to approximately 26 months
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Secondary outcome [1]
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Part 1: Area under the concentration-time curve (AUC) for GSK4418959
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Assessment method [1]
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Timepoint [1]
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From first day of dosing for the duration of treatment until end of interventional phase (EOI) (up to approximately 42 months)
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Secondary outcome [2]
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Part 1: Maximum concentration (Cmax) for GSK4418959
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Assessment method [2]
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0
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Timepoint [2]
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From first day of dosing for the duration of treatment until end of interventional phase (EOI) (up to approximately 42 months)
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Secondary outcome [3]
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Part 1: Time to maximum concentration (Tmax) for GSK4418959
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Assessment method [3]
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Timepoint [3]
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From first day of dosing for the duration of treatment until end of interventional phase (EOI) (up to approximately 42 months)
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Secondary outcome [4]
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Part 3: AUC for GSK4418959
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Assessment method [4]
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Timepoint [4]
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From first day of dosing for the duration of treatment until end of interventional phase (EOI) (up to approximately 42 months)
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Secondary outcome [5]
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Part 3: Cmax for GSK4418959
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Assessment method [5]
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Timepoint [5]
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From first day of dosing for the duration of treatment until end of interventional phase (EOI) (up to approximately 42 months)
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Secondary outcome [6]
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Part 3: Tmax for GSK4418959
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Assessment method [6]
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Timepoint [6]
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From first day of dosing for the duration of treatment until end of interventional phase (EOI) (up to approximately 42 months)
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Secondary outcome [7]
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Part 1: Number of participants with TEAEs
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Assessment method [7]
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Timepoint [7]
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Up to approximately 42 months
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Secondary outcome [8]
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Part 2: Number of participants with TEAEs
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Assessment method [8]
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Timepoint [8]
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Up to approximately 42 months
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Secondary outcome [9]
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Part 3: Number of participants with TEAEs
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Assessment method [9]
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Timepoint [9]
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Up to approximately 42 months
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Secondary outcome [10]
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Part 1: Number of participants with dosage interruptions, dose reductions, and drug discontinuations for TEAEs
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Assessment method [10]
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Timepoint [10]
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Up to approximately 42 months
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Secondary outcome [11]
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Part 2: Number of participants with dosage interruptions, dose reductions, and drug discontinuations for TEAEs
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Assessment method [11]
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Timepoint [11]
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Up to approximately 42 months
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Secondary outcome [12]
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Part 3: Number of participants with dosage interruptions, dose reductions, and drug discontinuations for TEAEs
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Assessment method [12]
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Timepoint [12]
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Up to approximately 42 months
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Secondary outcome [13]
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Part 1: Number of participants with clinical laboratory abnormalities
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Assessment method [13]
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Timepoint [13]
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Up to approximately 42 months
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Secondary outcome [14]
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Part 2: Number of participants with clinical laboratory abnormalities
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Assessment method [14]
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Timepoint [14]
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Up to approximately 42 months
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Secondary outcome [15]
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Part 3: Number of participants with clinical laboratory abnormalities
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Assessment method [15]
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Timepoint [15]
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Up to approximately 42 months
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Secondary outcome [16]
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Part 2: Progression-free Survival (PFS)
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Assessment method [16]
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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.
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Timepoint [16]
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Up to approximately 42 months
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Secondary outcome [17]
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Part 2: Duration of Response (DoR)
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Assessment method [17]
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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.
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Timepoint [17]
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Up to approximately 42 months
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Secondary outcome [18]
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Part 2: Plasma concentration of GSK4418959
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Assessment method [18]
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Timepoint [18]
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From first day of dosing for the duration of treatment until end of interventional phase (EOI) (up to approximately 42 months)
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Eligibility
Key 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
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Minimum age
18
Years
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Maximum age
No limit
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Sex
Both males and females
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Can healthy volunteers participate?
No
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Key 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
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Study design
Purpose of the study
Treatment
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Allocation to intervention
Non-randomised trial
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Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
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Methods used to generate the sequence in which subjects will be randomised (sequence generation)
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Masking / blinding
Open (masking not used)
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Who is / are masked / blinded?
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Intervention assignment
Other
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Other design features
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Phase
Phase 1
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Type of endpoint/s
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Statistical methods / analysis
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Recruitment
Recruitment status
Recruiting
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Data analysis
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Reason for early stopping/withdrawal
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Other reasons
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Date of first participant enrolment
Anticipated
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Actual
13/12/2024
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Date of last participant enrolment
Anticipated
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Actual
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Date of last data collection
Anticipated
16/06/2028
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Actual
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Sample size
Target
73
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Accrual to date
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Final
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Recruitment in Australia
Recruitment state(s)
VIC
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Recruitment hospital [1]
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GSK Investigational Site - Melbourne
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Recruitment postcode(s) [1]
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3000 - Melbourne
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Recruitment outside Australia
Country [1]
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United States of America
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State/province [1]
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Colorado
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Country [2]
0
0
United States of America
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State/province [2]
0
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Michigan
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Country [3]
0
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United States of America
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State/province [3]
0
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New York
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Country [4]
0
0
United States of America
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State/province [4]
0
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Pennsylvania
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Country [5]
0
0
Japan
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State/province [5]
0
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Chiba
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Country [6]
0
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Japan
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State/province [6]
0
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Shizuoka
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Country [7]
0
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Japan
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State/province [7]
0
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Tokyo
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Country [8]
0
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South Korea
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State/province [8]
0
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Daegu
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Country [9]
0
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South Korea
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State/province [9]
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Gyeonggi-do
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Country [10]
0
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South Korea
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State/province [10]
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Seoul
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Funding & Sponsors
Primary sponsor type
Commercial sector/industry
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Name
GlaxoSmithKline
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Address
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Country
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Other collaborator category [1]
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Commercial sector/industry
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Name [1]
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IDEAYA Biosciences
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Address [1]
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Country [1]
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Ethics approval
Ethics application status
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Summary
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.
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Trial website
https://clinicaltrials.gov/study/NCT06710847
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Trial related presentations / publications
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Public notes
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Contacts
Principal investigator
Name
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Address
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Country
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Phone
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Fax
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Email
0
0
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Contact person for public queries
Name
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US GSK Clinical Trials Call Center
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Address
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Country
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Phone
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877-379-3718
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Fax
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Email
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[email protected]
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Contact person for scientific queries
Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
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What data in particular will be shared?
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/
Supporting document/s available: Study protocol, Statistical analysis plan (SAP), Informed consent form (ICF), Clinical study report (CSR)
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When will data be available (start and end dates)?
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.
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Available to whom?
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.
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Available for what types of analyses?
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How or where can data be obtained?
IPD available at link: https://www.gsk.com/en-gb/innovation/trials/data-transparency/
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What supporting documents are/will be available?
No Supporting Document Provided
Results publications and other study-related documents
No documents have been uploaded by study researchers.
Results not provided in
https://clinicaltrials.gov/study/NCT06710847
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