A Phase 1 Clinical Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Clinical Activity of GSK5764227 as Monotherapy and in Combination in Participants With Advanced Solid Tumors
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 845
- 试验地点
- 67
- 主要终点
- Phase 1a: Number of participants with Adverse Events (AEs)
研究概览
简要总结
The goal of this study is to assess the safety, tolerability, clinical activity and pharmacokinetics of Risvutatug rezetecan (Ris-Rez), also known as GSK5764227. The study will also see how the levels of Ris-Rez will change over time at different dose amounts when administered alone and in combination with other medicines like carboplatin, cisplatin, atezolizumab, pembrolizumab, durvalumab, bevacizumab, cetuximab, tarlatamab, dostarlimab
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
- •Male or female participants at least 18 years of age (≥18 years)
- •Participants with histologically confirmed advanced/metastatic solid tumors, as defined per study phase and cohort, as follows:
- •Participants with advanced/metastatic solid tumors.
- •For monotherapy dose escalation: participants must have progressed on or become intolerant to all available SOC therapies.
- •For combination dose escalation: participants must have received 3 or fewer prior lines of systemic anticancer therapy in the advanced/metastatic setting
- •Has at least 1 target lesion per RECIST 1.1, as determined by the investigator.
- •Has an ECOG performance status of 0 or 1, with no deterioration in the 2 weeks before first dose.
- •Has adequate organ function.
- •Where available, participants should provide a formalin fixed and paraffin embedded (FFPE) tumor sample from the most recent biopsy of primary cancer or from a metastatic site for central testing.
排除标准
- •Has ongoing adverse reaction(s) from prior therapy that has(have) not recovered to ≤Grade 1 or to the baseline status preceding prior therapy.
- •Prior treatment with orlotamab, enoblituzumab, I-Dxd, or other B7-H3 targeted agents.
- •Primary brain tumor or evidence of brain metastasis (unless meeting the following criteria at the same time: asymptomatic; medically stable for at least 4 weeks prior to initial dosing; no steroid treatment required for at least 4 weeks prior to initial dosing; and no midline shift due to herniation); or untreated progression due to brain metastasis or primary brain tumor during or after the last treatment prior to screening; or evidence of meningeal/brainstem involvement; or evidence of spinal cord compression (detected by radiographic examination, symptomatic or not).
- •Any of the following cardiac examination abnormality:
- •Has QT interval, corrected for heart rate (QTc) >450 msec or QTc >480 msec for participants with bundle branch block.
- •Evidence of current clinically significant arrhythmias or ECG abnormalities (e.g., complete left bundle branch block, third-degree atrioventricular [AV] block, second-degree AV block, PR interval >250 msec).
- •Risk factors of prolonged QTc or arrhythmia events, such as heart failure, refractory hypokalemia, congenital long QT syndrome, family history of long QT syndrome, or unexplained sudden death of any direct relative under 40 years old or any concomitant medications that prolong the QT interval.
- •Left ventricular ejection fraction (LVEF) <50%.
- •Has severe, uncontrolled or active CV disorders, serious or poorly controlled hypertension, clinically significant bleeding symptoms or serious arteriovenous thromboembolic events
- •Participants with evidence of current ILD/non-infectious pneumonitis OR a prior history of ILD/non-infectious pneumonitis requiring high-dose glucocorticoids OR suspected ILD/non-infectious pneumonitis that cannot be ruled out by imaging.
- •Has a history of autoimmune disease that has required systemic treatments in the 2 years prior to screening. Participants with prior history of autoimmune disease must be discussed with the medical monitor. Replacement therapy is not considered a form of systemic therapy (e.g., thyroid hormone for autoimmune thyroiditis or insulin is not exclusionary).
- •Has any history of prior allogenic or autologous bone marrow transplant or other solid organ transplant.
- •Has received prior anticancer therapy within 28 days of the first dose of study intervention or having to continue these medications during the study.
研究组 & 干预措施
Phase 1a- Dose escalation- Combination therapy
干预措施: Cisplatin (Drug)
Phase 1a- Dose escalation- Combination therapy
干预措施: Carboplatin (Drug)
Phase 1a- Dose escalation- Combination therapy
干预措施: Atezolizumab (Biological)
Phase 1a- Dose escalation- Combination therapy
干预措施: Pembrolizumab (Biological)
Phase 1a- Dose escalation- Combination therapy
干预措施: Durvalumab (Biological)
Phase 1a- Dose escalation- Combination therapy
干预措施: Cetuximab (Biological)
Phase 1a- Dose escalation- Combination therapy
干预措施: Bevacizumab (Biological)
结局指标
主要结局
Phase 1a: Number of participants with Adverse Events (AEs)
时间窗: Up to approximately 28 months
Phase 1a: Number of participants with Dose Limiting Toxicities (DLTs)
时间窗: Up to 21 days
Phase 1a: Number of participants with AEs, serious adverse events (SAEs) and adverse events of special interest (AESIs) by severity
时间窗: Up to approximately 30 months
Phase 1a: Number of participants with AEs leading to dose modifications
时间窗: Up to approximately 28 months
Phase 1a: Number of participants with changes in vital signs, body weight, laboratory tests, electrocardiogram (ECG) and Eastern Cooperative Oncology Group (ECOG) performance status
时间窗: Up to approximately 28 months
Phase 1b: Confirmed Objective Response Rate (cORR)
时间窗: Up to approximately 27 months
cORR is defined as the proportion of participants who have confirmed Complete response (CR) or Partial response (PR), assessed by the investigator according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST V1.1) criteria or other imaging criteria for defined tumor types.
Phase 1a: Number of participants with Adverse Events (AEs)
时间窗: Up to approximately 28 months
Phase 1a: Number of participants with Dose Limiting Toxicities (DLTs)
时间窗: Up to 21 days
Phase 1a: Number of participants with AEs, serious adverse events (SAEs) and adverse events of special interest (AESIs) by severity
时间窗: Up to approximately 30 months
Phase 1a: Number of participants with AEs leading to dose modifications
时间窗: Up to approximately 28 months
Phase 1a: Number of participants with changes in vital signs, body weight, laboratory tests, electrocardiogram (ECG) and Eastern Cooperative Oncology Group (ECOG) performance status
时间窗: Up to approximately 28 months
Phase 1b: Confirmed Objective Response Rate (cORR)
时间窗: Up to approximately 27 months
cORR is defined as the proportion of participants who have confirmed Complete response (CR) or Partial response (PR), assessed by the investigator according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST V1.1) criteria or other imaging criteria for defined tumor types.
次要结局
- Phase 1b: Proportion of Participants with Tumour antigen Decrease From Baseline >=50% response rate(Up to approximately 33 months)
- Phase 1b: Number of participants with AEs leading to dose modifications(Up to approximately 27 months)
- Phase 1a and Phase 1b: Trough concentration (Ctrough) of GSK5757810 (small-molecule toxin)(Up to approximately 28 months)
- Phase 1a: Confirmed Objective Response Rate (cORR)(Up to approximately 33 months)
- Phase 1a: Disease control rate at 12 weeks (DCR12)(At 12 weeks)
- Phase 1b: Disease control rate at 12 weeks (DCR12)(At 12 weeks)
- Phase 1b: Duration of Response (DoR)(Up to approximately 33 months)
- Phase 1b: Progression-Free Survival (PFS)(Up to approximately 33 months)
- Phase 1a and Phase 1b: Maximum concentration (Cmax) of GSK5764227(Up to approximately 28 months)
- Phase 1a and Phase 1b: Time to reach maximum concentration (Tmax) of GSK5764227(Up to approximately 28 months)
- Phase 1a and Phase 1b: Area under the curve (AUC) of GSK5764227(Up to approximately 28 months)
- Phase 1a and Phase 1b: Trough concentration (Ctrough) of GSK5764227 (conjugated antibody)(Up to approximately 28 months)
- Phase 1a and Phase 1b: Trough concentration (Ctrough) of GSK5764227 (total antibody)(Up to approximately 28 months)
- Phase 1a and Phase 1b: Trough concentration (Ctrough) of GSK5757810 (small-molecule toxin)(Up to approximately 28 months)
- Phase 1a: Confirmed Objective Response Rate (cORR)(Up to approximately 33 months)
- Phase 1a: Disease control rate at 12 weeks (DCR12)(At 12 weeks)
- Phase 1b: Disease control rate at 12 weeks (DCR12)(At 12 weeks)
- Phase 1a: Duration of Response (DoR)(Up to approximately 33 months)
- Phase 1b: Duration of Response (DoR)(Up to approximately 33 months)
- Phase 1b: Proportion of Participants with Tumour antigen Decrease From Baseline >=50% response rate(Up to approximately 33 months)
- Phase 1a and Phase 1b: Number of participants with Antidrug antibody (ADA) or Neutralizing Antibody (NAb)(Up to approximately 30 months)
- Phase 1a and Phase 1b: Titers of ADA against GSK5764227(Up to approximately 30 months)
- Phase 1b: Number of participants with AEs, SAEs and AESI by severity(Up to approximately 30 months)
- Phase 1b: Number of participants with AEs leading to dose modifications(Up to approximately 27 months)
- Phase 1b: Number of participants with changes in vital signs, body weight, laboratory tests, ECG, ECHO and ECOG performance status(Up to approximately 28 months)
- Phase 1b: Progression-Free Survival (PFS)(Up to approximately 33 months)