Sirolimus for the Treatment of Severe Intestinal Polyposis in Patients With Familial Adenomatous Polyposis (FAP): a Pilot Study
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 4
- 试验地点
- 1
- 主要终点
- Change in Marked Polyp Size
研究概览
简要总结
The aim of the study is to investigate the effect of sirolimus on the progression of intestinal adenomas in patients with FAP and to assess the safety of this treatment.
详细描述
SUMMARY Rationale: Due to the presence of numerous colorectal polyps, nearly all patients with familial adenomatous polyposis (FAP) develop colorectal cancer (CRC) at an average age of 45 years, if left untreated. Therefore, a prophylactic colectomy is recommended. After surgery, adenomas are likely to reappear in the pouch or rectum. Recently, studies in APC-deficient mice have shown that the mTOR inhibitor sirolimus can cause intestinal tumour cells to undergo growth arrest and differentiation and could even lead to regression of polyps. In current practice, sirolimus is used as an immunomodulator for patients after renal transplantation. Sirolimus has never been investigated in patients with FAP. The hypothesis of the study is that sirolimus could lead to regression of intestinal polyps in patients with FAP.
Objective: The aim of the study is to investigate the effect of sirolimus on the progression of intestinal adenomas in patients with FAP and to assess the safety of this treatment.
Study design: A prospective phase II pilot study with a follow-up of 6 months. Study population: Five patients with FAP will be selected and invited for study participation. Patients need to be 18 years or older, have a genetically confirmed APC mutation with a classical FAP phenotype and a subtotal colectomy with an ileo-rectal anastomosis (IRA) or a total colectomy with an ileo-anal pouch anastomosis (IPAA) with severe polyposis.
Intervention: All patients will receive sirolimus for the duration of the study, with a trough level target range of 5-8 ng/ml.
Main study parameters/endpoints: The main study parameters are the effect of sirolimus on the size of 5 marked polyps and safety of this treatment. Safety outcomes will be assessed by summary analysis of adverse events, clinical laboratory abnormalities and regular physical examination. Additional parameters are the effect on the number of polyps, global polyp burden, histopathology and patient-reported quality of life. Cell proliferation and immunohistochemistry of mTOR targets in healthy intestinal mucosa and adenomatous tissue will be assessed.
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
- •≥ 18 years
- •A genetically confirmed APC mutation
- •Classical FAP phenotype (100-1000 colorectal adenomatous polyps)
- •Subtotal colectomy with ileorectal anastomosis (IRA) or total colectomy with ileo-anal pouch anastomosis (IPAA)
- •Severe rectal or pouch polyposis, defined as having >25 polyps amenable to complete removal (InSiGHT 2011 Staging System score of 3)
- •Fertile patients must use effective contraception during study treatment and until 12 weeks after study treatment
排除标准
- •Inability to give informed consent
- •Participation in another interventional clinical trial
- •Subjects who are pregnant or breast-feeding, proved with a negative pregnancy test if female of child-bearing potential
- •Prior pelvic irradiation
- •Invasive malignancy in the past 5 years
- •Subjects who are HIV positive
- •Subjects with severe systemic infections, current or within 2 weeks prior to study start
- •Subjects with known severe restrictive or obstructive pulmonary disorders
- •Known sucrase insufficiency, isomaltase insufficiency, fructose intolerance, glucose malabsorption, galactose malabsorption, galactose intolerance or Lapp-lactase deficiency
- •History of pulmonary embolism or deep venous thrombosis
- •Major surgery less than or equal to 2 weeks prior to enrollment or any planned surgery within treatment period
- •Active post-operative complication, e.g. infection, delayed wound healing
- •History of hypersensitivity to sirolimus or to drugs of similar chemical classes
- •Regular NSAID use (defined as more than twice a week for 4 consecutive weeks) within 3 months prior to baseline
- •Use of other FAP directed drug therapies (accepted if discontinued 3 months prior to start of the study)
- •Subjects requiring systemic anticoagulation
- •Co-medication that could interact with sirolimus
- •Abnormal laboratory results (assessed within 14 days prior to start of study drug)
研究组 & 干预措施
Sirolimus
All patients will receive sirolimus for the duration of the study, with a trough level target range of 5-8 ng/ml.
干预措施: Sirolimus (Drug)
结局指标
主要结局
Change in Marked Polyp Size
时间窗: 6 Months
Effect of sirolimus on the size of 5 marked polyps per patient based on video observations.
Median Number of Treatment-Related Adverse Events Per Participant
时间窗: 6 Months
Summary analysis of adverse events, clinical laboratory abnormalities and regular physical examination.
次要结局
- Median Difference in Number of Intestinal Polyps(6 Months)
- Global Polyp Burden(6 Months)
研究者
Prof. Evelien Dekker, MD, PhD
Professor MD
Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)