Investigator-initiated Phase I Study of a Tankyrase Inhibitor RK-582 for Patients With Unresectable Metastatic Colorectal Cancer
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 发起方
- 入组人数
- 48
- 试验地点
- 1
- 主要终点
- Percentage of dose-limiting toxicity
研究概览
简要总结
Tankyrase, the fifth and sixth members of the poly(ADP-ribose) polymerase (PARP) family (PARP-5a/b), is responsible for poly(ADP-ribosyl)ation (PARylation), and was originally identified as a factor that promotes the function of telomerase, an enzyme that elongates telomeres. Subsequently, it was reported that tankyrase enhances Wnt/beta-catenin signaling by PARylation and subsequent degradation of AXIN, a negative regulator of Wnt/beta-catenin signaling, suggesting that tankyrase inhibitors may be a new treatment for colorectal cancer.
RK-582 was discovered through lead optimization from a tankyrase inhibitor that suppresses the growth of human colorectal cancer cells. It was confirmed that RK-582 selectively inhibited tankyrase among the PARP family enzymes, suppressed the growth of Wnt/beta-catenin signal-dependent human colorectal cancer cells at both the levels of cultured cells and xenograft tumors in immunodeficient mice, and accumulated AXIN to decrease beta-catenin and downregulate the target gene expression as pharmacodynamic biomarkers.
Based on these findings, RK-582 is thought to have potential as a new treatment for colorectal cancer patients. At present, however, the efficacy and safety of RK-582 in humans have not been confirmed. Thus, this clinical trial is conducted with the aim of investigating the tolerability and safety of RK-582 for patients with unresectable advanced or recurrent colorectal cancer as a first-in-human trial, in which RK-582 is administered to humans for the first time.
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 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patients with histologically or cytologically diagnosed colorectal cancer
- •Patients who are refractory or intolerant to standard treatment for unresectable advanced or recurrent colorectal cancer
- •Patients with measurable disease according to RECIST guideline ver 1.1
- •Patients who are able to take capsules orally
排除标准
- •Patients with clinically relevant gastrointestinal, hepatic, musculoskeletal, respiratory, cerebral/cardiovascular, hematologic, oncologic, endocrine, immunologic, psychiatric, neurologic, or genitourinary diseases, or patients with conditions that are judged to threaten the safety of the participant or to affect the outcome of this clinical trial by the investigators
- •Patients with medical history of interstitial lung disease
- •Patients with chronic nausea, vomiting or diarrhea that may interfere with oral administration of the investigational drug
- •Patients with pulmonary embolism or central deep vein thrombosis.
- •Patients receiving treatment with strong CYP3A4 inhibitors or inducers.
- •Patients diagnosed and treated for osteoporosis or patients with a bone mineral density of less than T-score -2.5 at the time of screening
- •Patients with obvious bone metastases in the long bones, vertebrae, or other parts of the leg where gravity is applied
研究组 & 干预措施
RK-582
干预措施: RK-582 (Drug)
结局指标
主要结局
Percentage of dose-limiting toxicity
时间窗: 35 days after the first dose of RK-582
Number of participants with adverse events as assessed by CTCAE v5.0
时间窗: Approximately 1 year after the first dose of RK-582
次要结局
- Area under the curve (AUC) after single or repeated dosing(22 days after the first dose of RK-582)
- Maximum plasma concentration (Cmax) after single or repeated dosing(22 days after the first dose of RK-582)
- Maximum concentration time (Tmax) after single or repeated dosing(22 days after the first dose of RK-582)
- Elimination rate constant (kel) after single or repeated dosing(22 days after the first dose of RK-582)
- Elimination half-life (t1/2) after single or repeated dosing(22 days after the first dose of RK-582)
- Apparent total body clearance (CLtot/F) after single or repeated dosing(22 days after the first dose of RK-582)
- Apparent volume of distribution (Vd/F) after single or repeated dosing(22 days after the first dose of RK-582)
- Objective response rate based on investigator's judgment as assessed by RECIST guideline ver. 1.1(Approximately 1 year after the first dose of RK-582)
- Percentage of subjects who achieved a complete or partial response on the best overall response as assessed by RECIST guideline ver. 1.1(Approximately 1 year after the first dose of RK-582)
- Duration of response as assessed by RECIST guideline ver. 1.1(Approximately 1 year after the first dose of RK-582)
- Disease control rate as assessed by RECIST guideline ver. 1.1(Approximately 1 year after the first dose of RK-582)
- Time to response as assessed by RECIST guideline ver. 1.1(Approximately 1 year after the first dose of RK-582)
- Progression-free survival as assessed by RECIST guideline ver. 1.1(Approximately 1 year after the first dose of RK-582)
- Overall survival(Approximately 30 months after the first dose of RK-582)
研究者
Eiji Shinozaki
Vice Director of Gastroenterological Chemotherapy Department
Japanese Foundation for Cancer Research