NCT06710847进行中（未招募）1 期
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)
适应症
干预措施
相关药物
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 入组人数
- 14
- 试验地点
- 23
- 主要终点
- Part 1: Number of participants with dose limiting toxicities (DLTs) during DLT observation period
研究概览
简要总结
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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 0-2
- •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
排除标准
- •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
研究组 & 干预措施
Part 1: Dose escalation of GSK4418959 monotherapy
Experimental
Participants will receive GSK4418959 as monotherapy.
干预措施: GSK4418959 (Drug)
Part 2: Dose expansion of GSK4418959 monotherapy
Experimental
Participants will receive GSK4418959 as monotherapy.
干预措施: GSK4418959 (Drug)
Part 3: Dose escalation of GSK4418959 plus PD-1 inhibitor
Experimental
Participants will receive GSK4418959 plus PD-1 inhibitor.
干预措施: GSK4418959 (Drug)
Part 3: Dose escalation of GSK4418959 plus PD-1 inhibitor
Experimental
Participants will receive GSK4418959 plus PD-1 inhibitor.
干预措施: PD-1 inhibitor (Biological)
结局指标
主要结局
Part 1: Number of participants with dose limiting toxicities (DLTs) during DLT observation period
时间窗: Up to 21 days
Part 3: Number of participants with dose limiting toxicities (DLTs) during DLT observation period
时间窗: Up to 21 days
Part 1: Number of participants with treatment emergent adverse events (TEAEs) during DLT observation period
时间窗: Up to 21 days
Part 3: Number of participants with treatment emergent adverse events (TEAEs) during DLT observation period
时间窗: Up to 21 days
Part 1: Number of participants with dosage interruptions, dose reductions, and drug discontinuations for TEAEs during DLT observation period
时间窗: Up to 21 days
Part 3: Number of participants with dosage interruptions, dose reductions, and drug discontinuations for TEAEs during DLT observation period
时间窗: Up to 21 days
Part 2: Objective Response Rate (ORR)
时间窗: 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.
次要结局
- 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)
- Part 2: Duration of Response (DoR)(Up to approximately 42 months)
- 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))
研究者
研究点 (23)
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