FTIH study to investigate the safety and preliminary efficacy of the DNA-repair inhibitor GSK4418959 alone or in combination with other anti-cancer agents in dMMR/MSI-H solid tumors

JRCT ID: jRCT2031240500

Registered date:21/11/2024

Basic Information

• Recruitment status: Pending
• Health condition(s) or Problem(s) studied: Mismatch Repair-deficient (dMMR) or Microsatellite Instability-High (MSI-H) solid tumor
• Date of first enrollment: 19/12/2024
• Target sample size: 7
• Countries of recruitment: United States,Japan,Australia,Japan
• Study type: Interventional

Intervention(s)

Drug: GSK4418959
Drug:PD-1 inhibitor

Outcome(s)

Primary Outcome

Part 1, Part 3:
- Number of participants with dose limiting toxicities (DLTs) during DLT observation period,
- Number of participants with treatment emergent adverse events (TEAEs) during DLT observation period,
- Number of participants with dosage interruptions, dose reductions, and drug discontinuations for TEAEs during DLT observation period

Part 2: Objective Response Rate (ORR)

Secondary Outcome

Part 1, 2, 3
- Number of participants with TEAEs
- Number of participants with dosage interruptions, dose reductions, and drug discontinuations for TEAEs
- Number of participants with clinical laboratory abnormalities

Part 1, Part 3:
- Area under the concentration-time curve (AUC) for GSK4418959,
- Maximum concentration (Cmax) for GSK4418959,
- Time to maximum concentration (Tmax) for GSK4418959,

Part 2:
- Progression-free Survival (PFS)
- Duration of Response (DoR)
- Plasma concentration of GSK4418959

Key inclusion & exclusion criteria

• Age minimum: >= 18age old
• Age maximum: Not applicable
• Gender: Both

Include 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

Exclude 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

Related Information

• Primary Sponsor: Ishibashi Hideyasu
• Source(s) of Monetary Support: IDEAYA Biosciences