Clinical trial NCT06710847: 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
Official 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)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: Neoplasms, Colorectal
Solid Tumor
Colon Cancer
Rectal Cancer
Endometrial Cancer
Keywords: GSK4418959
DNA Helicase Werner Inhibitor (WRNi)
PD-1 inhibitor
Solid tumors
Colon cancer
Rectal cancer
Colorectal cancer
Endometrial cancer
Mismatch repair deficient
dMMR
microsatellite instability high
MSI-H
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
Collaborators: name: IDEAYA Biosciences
First posted: 2024-11-29
Enrollment: 73
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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.


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

Primary outcomes:
measure: Part 1: Number of participants with dose limiting toxicities (DLTs) during DLT observation period
timeFrame: Up to 21 days
measure: Part 3: Number of participants with dose limiting toxicities (DLTs) during DLT observation period
timeFrame: Up to 21 days
measure: Part 1: Number of participants with treatment emergent adverse events (TEAEs) during DLT observation period
timeFrame: Up to 21 days
measure: Part 3: Number of participants with treatment emergent adverse events (TEAEs) during DLT observation period
timeFrame: Up to 21 days
measure: Part 1: Number of participants with dosage interruptions, dose reductions, and drug discontinuations for TEAEs during DLT observation period
timeFrame: Up to 21 days
measure: Part 3: Number of participants with dosage interruptions, dose reductions, and drug discontinuations for TEAEs during DLT observation period
timeFrame: Up to 21 days
measure: Part 2: Objective Response Rate (ORR)
timeFrame: Up to approximately 26 months
Secondary outcomes:
measure: Part 1: Area under the concentration-time curve (AUC) for GSK4418959
timeFrame: From first day of dosing for the duration of treatment until end of interventional phase (EOI) (up to approximately 42 months)
measure: Part 1: Maximum concentration (Cmax) for GSK4418959
timeFrame: From first day of dosing for the duration of treatment until end of interventional phase (EOI) (up to approximately 42 months)
measure: Part 1: Time to maximum concentration (Tmax) for GSK4418959
timeFrame: From first day of dosing for the duration of treatment until end of interventional phase (EOI) (up to approximately 42 months)
measure: Part 3: AUC for GSK4418959
timeFrame: From first day of dosing for the duration of treatment until end of interventional phase (EOI) (up to approximately 42 months)
measure: Part 3: Cmax for GSK4418959
timeFrame: From first day of dosing for the duration of treatment until end of interventional phase (EOI) (up to approximately 42 months)
measure: Part 3: Tmax for GSK4418959
timeFrame: From first day of dosing for the duration of treatment until end of interventional phase (EOI) (up to approximately 42 months)
measure: Part 1: Number of participants with TEAEs
timeFrame: Up to approximately 42 months
measure: Part 2: Number of participants with TEAEs
timeFrame: Up to approximately 42 months
measure: Part 3: Number of participants with TEAEs
timeFrame: Up to approximately 42 months
measure: Part 1: Number of participants with dosage interruptions, dose reductions, and drug discontinuations for TEAEs
timeFrame: Up to approximately 42 months
measure: Part 2: Number of participants with dosage interruptions, dose reductions, and drug discontinuations for TEAEs
timeFrame: Up to approximately 42 months
measure: Part 3: Number of participants with dosage interruptions, dose reductions, and drug discontinuations for TEAEs
timeFrame: Up to approximately 42 months
measure: Part 1: Number of participants with clinical laboratory abnormalities
timeFrame: Up to approximately 42 months
measure: Part 2: Number of participants with clinical laboratory abnormalities
timeFrame: Up to approximately 42 months
measure: Part 3: Number of participants with clinical laboratory abnormalities
timeFrame: Up to approximately 42 months
measure: Part 2: Progression-free Survival (PFS)
timeFrame: Up to approximately 42 months
measure: Part 2: Duration of Response (DoR)
timeFrame: Up to approximately 42 months
measure: Part 2: Plasma concentration of GSK4418959
timeFrame: From first day of dosing for the duration of treatment until end of interventional phase (EOI) (up to approximately 42 months)
Other outcomes:
Locations:
city: Denver
country: United States
facility: GSK Investigational Site
state: Colorado
city: Chiba
country: Japan
facility: GSK Investigational Site
city: Tokyo
country: Japan
facility: GSK Investigational Site
city: Tokyo
country: Japan
facility: GSK Investigational Site
Study officials:
References: