A Phase Ib/II Study of the Safety, Tolerability, and Efficacy of a Pan-RAS Inhibitor in Combination With Anti-Tumor Therapy in Participants With Advanced Pancreatic Cancer
试验速览
- 阶段
- 1 期
- 状态
- 尚未招募
- 发起方
- 入组人数
- 80
- 试验地点
- 1
- 主要终点
- Objective Response Rate
研究概览
简要总结
This study aims to evaluate the safety, tolerability, and efficacy of HRS-2329 in combination with other anti-tumor therapies in participants with advanced pancreatic cancer harboring RAS mutations or amplifications.
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
- •Age ≥ 18 years.
- •Histopathologically confirmed locally advanced or metastatic pancreatic adenocarcinoma (originating from pancreatic ductal epithelium) that is not amenable to curative therapy.
- •RAS mutation or amplification detected in tumor tissue or blood (by RAS testing).
- •Prior anti-tumor therapy:
- •For cohort HRS-2329-A: at least one line of standard systemic therapy in the advanced setting;
- •For cohorts HRS-2329-B and HRS-2329-C: at most one line of standard systemic therapy in the advanced setting.
- •At least one measurable lesion according to RECIST version 1.1 criteria.
- •Eastern Cooperative Oncology Group (ECOG) performance status score of 0-
- •Life expectancy ≥ 3 months.
- •Adequate function of vital organs.
- •Use of appropriate contraceptive methods during the study period, and so forth.
- •Voluntary participation in this study with signed informed consent, good compliance, and willingness to cooperate with follow-up assessments.
排除标准
- •Prior treatment with drugs similar to the investigational product.
- •Known presence of central nervous system (CNS) metastases.
- •Acute or chronic pancreatitis requiring clinical intervention.
- •Gastrointestinal disorders that may affect drug administration/absorption, including but not limited to dysphagia, malabsorption syndrome, refractory nausea, vomiting, or diarrhea, Crohn's disease, and ulcerative colitis.
- •Gastrointestinal obstruction, or signs/symptoms of gastrointestinal obstruction; however, patients who have undergone surgical intervention with complete resolution of the obstruction may be considered for screening.
- •Concurrent biliary obstruction with risk of biliary tract infection (patients with treatable biliary obstruction may be enrolled if adequate biliary drainage is achieved and the risk of biliary infection is resolved after treatment).
- •Third-space fluid collections (e.g., massive pleural effusion, ascites) that cannot be stabilised (i.e., no intervention required after drainage removal) within 2 weeks prior to enrolment; patients with only a small amount of fluid detected by imaging and without clinical symptoms may be enrolled.
- •Severe infection within 4 weeks prior to enrolment, such as severe pneumonia, bacteraemia, or infectious complications requiring hospitalisation; unexplained fever >38.5°C within 2 weeks prior to enrolment ; signs/symptoms of infection requiring intravenous antibiotic therapy within 2 weeks prior to enrolment.
- •Severe cardiovascular or cerebrovascular diseases.
- •Known or suspected interstitial lung disease (isolated imaging findings of interstitial changes are not excluded).
- •History of definite neurological or psychiatric disorders, including epilepsy and dementia.
- •Non-healing wounds (severe, non-healing, or dehiscent), or unhealed fractures.
- •Adverse events from prior therapy not recovered to NCI-CTCAE Grade ≤1 at enrolment .
- •History of malignancies other than the primary tumour within 5 years prior to enrolment, with the exception of malignancies with low risk of metastasis and death, such as adequately treated carcinoma in situ of the cervix, basal cell carcinoma, or squamous cell carcinoma of the skin.
- •Active hepatitis B infection.
- •For Cohort C, conditions that are unsuitable for immunotherapy.
- •Known allergy to any component of any of the study drugs to be administered.
- •Any other condition that, in the investigator's judgement, may affect the study results or result in premature termination of the study.
研究组 & 干预措施
Arm A
This arm evaluates HRS-2329 in combination with nimotuzumab in participants with advanced pancreatic cancer harboring RAS mutations or amplifications who have received at least one prior line of therapy. Approximately 6 to 10 participants are planned to be enrolled initially to assess safety and preliminary efficacy, at the prespecified dose of HRS-2329 plus nimotuzumab 400 mg (D1,D8,Q3W). If the safety at this dose level is acceptable, enrollment may be expanded to 15-20 participants. During this period, the Safety Monitoring Committee (SMC) may review the cumulative safety and efficacy data and, after discussion, decide whether to adjust the dose, add other dose groups or dosing frequency arms for further exploration, or discontinue this combination regimen.
干预措施: HRS-2329 Tablet (Drug)
Arm C
Alternative arm: This arm evaluates HRS-2329 and HS-20093 in combination with adebrelimab in participants with advanced pancreatic cancer harboring RAS mutations or amplifications who are treatment-naïve or have received up to one prior line of standard systemic therapy. Approximately 30 participants are planned to be enrolled. The prespecified doses are HRS-2329 plus HS-20093 plus adebrelimab 1200 mg Q3W. The Safety Monitoring Committee (SMC) may review the cumulative safety and efficacy data and, after discussion, decide whether to adjust the dose, add other dose groups or dosing frequency arms for further exploration, or discontinue this combination regimen.
干预措施: Adebrelimab (Drug)
Arm A
This arm evaluates HRS-2329 in combination with nimotuzumab in participants with advanced pancreatic cancer harboring RAS mutations or amplifications who have received at least one prior line of therapy. Approximately 6 to 10 participants are planned to be enrolled initially to assess safety and preliminary efficacy, at the prespecified dose of HRS-2329 plus nimotuzumab 400 mg (D1,D8,Q3W). If the safety at this dose level is acceptable, enrollment may be expanded to 15-20 participants. During this period, the Safety Monitoring Committee (SMC) may review the cumulative safety and efficacy data and, after discussion, decide whether to adjust the dose, add other dose groups or dosing frequency arms for further exploration, or discontinue this combination regimen.
干预措施: Nimotuzumab (Drug)
Arm B
This arm evaluates HRS-2329 and HS-20093 with or without nimotuzumab in participants with advanced pancreatic cancer harboring RAS mutations or amplifications who are treatment-naïve or have received up to one prior line of standard systemic therapy. Approximately 30 participants are planned to be enrolled. The prespecified doses are HRS-2329 plus HS-20093, with or without nimotuzumab 400 mg on Day 1 and Day 8 of each 3-week cycle. The Safety Monitoring Committee (SMC) may review the cumulative safety and efficacy data and, after discussion, decide whether to adjust the dose, add other dose groups or dosing frequency arms for further exploration, or discontinue this combination regimen.
干预措施: HRS-2329 Tablet (Drug)
Arm C
Alternative arm: This arm evaluates HRS-2329 and HS-20093 in combination with adebrelimab in participants with advanced pancreatic cancer harboring RAS mutations or amplifications who are treatment-naïve or have received up to one prior line of standard systemic therapy. Approximately 30 participants are planned to be enrolled. The prespecified doses are HRS-2329 plus HS-20093 plus adebrelimab 1200 mg Q3W. The Safety Monitoring Committee (SMC) may review the cumulative safety and efficacy data and, after discussion, decide whether to adjust the dose, add other dose groups or dosing frequency arms for further exploration, or discontinue this combination regimen.
干预措施: HRS-2329 Tablet (Drug)
Arm B
This arm evaluates HRS-2329 and HS-20093 with or without nimotuzumab in participants with advanced pancreatic cancer harboring RAS mutations or amplifications who are treatment-naïve or have received up to one prior line of standard systemic therapy. Approximately 30 participants are planned to be enrolled. The prespecified doses are HRS-2329 plus HS-20093, with or without nimotuzumab 400 mg on Day 1 and Day 8 of each 3-week cycle. The Safety Monitoring Committee (SMC) may review the cumulative safety and efficacy data and, after discussion, decide whether to adjust the dose, add other dose groups or dosing frequency arms for further exploration, or discontinue this combination regimen.
干预措施: Nimotuzumab (Drug)
Arm B
This arm evaluates HRS-2329 and HS-20093 with or without nimotuzumab in participants with advanced pancreatic cancer harboring RAS mutations or amplifications who are treatment-naïve or have received up to one prior line of standard systemic therapy. Approximately 30 participants are planned to be enrolled. The prespecified doses are HRS-2329 plus HS-20093, with or without nimotuzumab 400 mg on Day 1 and Day 8 of each 3-week cycle. The Safety Monitoring Committee (SMC) may review the cumulative safety and efficacy data and, after discussion, decide whether to adjust the dose, add other dose groups or dosing frequency arms for further exploration, or discontinue this combination regimen.
干预措施: HS-20093 (Drug)
Arm C
Alternative arm: This arm evaluates HRS-2329 and HS-20093 in combination with adebrelimab in participants with advanced pancreatic cancer harboring RAS mutations or amplifications who are treatment-naïve or have received up to one prior line of standard systemic therapy. Approximately 30 participants are planned to be enrolled. The prespecified doses are HRS-2329 plus HS-20093 plus adebrelimab 1200 mg Q3W. The Safety Monitoring Committee (SMC) may review the cumulative safety and efficacy data and, after discussion, decide whether to adjust the dose, add other dose groups or dosing frequency arms for further exploration, or discontinue this combination regimen.
干预措施: HS-20093 (Drug)
结局指标
主要结局
Objective Response Rate
时间窗: From enrollment to upto 2 years
The proportion of patients whose tumor size shrinks as complete response or partial response, as assessed by RECIST1.1.
次要结局
- Disease Control Rate (DCR)(From enrollment to upto 2 years)
- Duration of Response(From enrollment to upto 2 years)
- Progression-Free Survival(From enrollment to upto 2 years)
- Overall Survival(From enrollment to upto 2 years)
- Adverse event(From enrollment to upto 2 years)
研究者
TingBo Liang
The chairman of the First Affiliated Hospital of Zhejiang University School of Medicine
Zhejiang University