Phase II Study to Evaluate the Efficacy and Safety of Sirolimus in Subjects With Metastatic, Mismatch Repair Deficient Solid Tumors After Immunotherapy
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 入组人数
- 6
- 试验地点
- 1
- 主要终点
- Objective Response Rate (ORR)
研究概览
简要总结
To evaluate the efficacy of sirolimus by estimating the overall response rate (ORR) as assessed by Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST v1.1) in patients with metastatic dMMR solid cancer after immunotherapy (either due to disease progression or to inability to tolerate treatment).
详细描述
Despite recent therapeutic strategies, including immunotherapy, treatment alternatives for patients with metastatic mismatch-repair deficient (dMMR) solid tumors remain scarce. Pre-clinical data suggests that dMMR tumors are susceptible to rapamycin (sirolimus), an mTOR inhibitor. In these tumors, characterized by higher levels of oxidative stress, sirolimus can exert a cytotoxic effect, led by the failure to repair DNA damage by inhibition of antioxidant enzymes such as FOXO3a triggered by Akt hyperactivation.
This proposal presents a phase 2 clinical trial designed to evaluate the efficacy of sirolimus in patients with dMMR solid tumors after immunotherapy. The investigators hypothesize that sirolimus will increase the overall response rate (ORR) by 20%.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Metastatic solid cancer tumor after immunotherapy (either due to progression of disease or inability to tolerate treatment)
- •dMMR by immunohistochemistry (IHC) defined as the loss of expression in any of the four major MMR proteins (MLH1, MSH2, MSH6 and PMS2) or by next- generation sequencing (NGS)
- •Age older than 18 at the time of informed consent
- •Eastern Cooperative Oncology Group performance status of 0-2
- •≥1 measurable lesion based on RECIST, version 1.1 (16)
- •Absolute neutrophil count (ANC) ≥1,500 mm3
- •Platelet count ≥75,000 mm3
- •Hemoglobin ≥ 9 g/dl
- •Aspartate aminotransferase (AST) ≤3.0 times the upper normal limit (UNL)
- •Alanine aminotransferase (ALT) ≤3.0 times the upper normal limit (UNL) Bilirubin ≤1.5 times the UNL
- •Serum creatinine ≤1.5 times the UNL
排除标准
- •Received immunotherapy in the prior 21 days.
- •Have not recovered from toxicities of prior treatments to at least grade
- •Symptomatic central nervous system (CNS) metastases
- •Pregnancy or Breast-feeding.
研究组 & 干预措施
Sirolimus
Participants will be instructed to take 2 milligrams (mg) every day for 28 days (1 cycle). They will be evaluated in the oncology clinic every 2 weeks to make sure they are tolerating the medication well.
干预措施: Sirolimus 2mg Tablet (Drug)
结局指标
主要结局
Objective Response Rate (ORR)
时间窗: Up to approximately 24 weeks after achieving therapeutic sirolimus levels, up to 7 months total
To evaluate the efficacy of sirolimus in patients with metastatic mismatch repair deficient (dMMR) solid cancer after immunotherapy (either due to disease progression or to inability to tolerate treatment), ORR will be determined. For this study ORR will be defined as the percentage of patients who achieve either a complete response (CR = disappearance of all target tumors); or a partial response (PR = ≥30% decrease in the sum of the longest diameters of target tumors) based on Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST v1.1) following review of imaging (CT-CAP or PET-CT) data.
次要结局
- Progression Free Survival (PFS)(Approximately 24 weeks after sirolimus initiation, up to approximately 7 months total)
- Response Duration (RD)(Up to ~24 weeks from the time of tumor response, up to 7 months total)
- Overall Survival (OS)(Approximately 24 weeks after sirolimus initiation, up to approximately 7 months total)