Clinical Trial: Sirolimus and Familial Adenomatous Polyposis (FAP)

Study Status: Recruiting
Recruit Status: Recruiting
Study Type: Interventional

Official Title: Sirolimus for the Treatment of Severe Intestinal Polyposis in Patients With Familial Adenomatous Polyposis (FAP): a Pilot Study

Brief Summary: 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.

Detailed Summary:

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 su
Sponsor: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

Current Primary Outcome:

  • Size of intestinal polyps [ Time Frame: 6 Months ]
    Effect of sirolimus on the size of 5 marked polyps
  • Number of participants with treatment-related adverse events [ Time Frame: 6 Months ]
    Summary analysis of adverse events, clinical laboratory abnormalities and regular physical examination.


Original Primary Outcome: Same as current

Current Secondary Outcome:

  • Number of intestinal polyps [ Time Frame: 6 Months ]
    Number of intestinal polyps is categorized per 10 polyps by the endoscopist and two independent reviewers, blinded for the order of videos (before and after treatment). The mean number of polyps is calculated as a mean of all 3 assessments. If the assessment between reviewers differs by more than 10 polyps from the assessment of the endoscopist, consensus is needed.
  • Global Polyp Burden [ Time Frame: 6 Months ]
    The global polyp burden is estimated by the endoscopist and two independent reviewers. The second video in the pair could take the value of −2 (much better), −1 (better), 0 (same), 1 (worse) or 2 (much worse) relative to the first video. Mean scores are calculated for each subject and averaged for the three reviewers. If the assessment of the reviewers differs by more than 1 point from the assessment of the endoscopist, consensus is needed.
  • Histology of intestinal polyps [ Time Frame: 6 Months ]
    Histology will be reported as tubular, tubulovillous or villous with'the degree of dysplasia.
  • Patient reported quality of life [ Time Frame: 6 Months ]
    Patient reported quality of life using HRQoL questionnaires
  • Rate of cell proliferation [ Time Frame: 6 Months ]
    Rate of cell proliferation in healthy intestinal mucosa and adenomatous tissue
  • Immunohistochemistry of mTOR targets [ Time Frame: 6 Months ]
    Immunohistochemistry of mTOR targets (such as eEF2 kinase, phospho-S6) in healthy intestinal mucosa and adenomatous tissue


Original Secondary Outcome: Same as current

Information By: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

Dates:
Date Received: March 21, 2017
Date Started: May 1, 2017
Date Completion: May 1, 2018
Last Updated: March 24, 2017
Last Verified: March 2017