Sirolimus and Familial Adenomatous Polyposis (FAP)

August 2, 2024 updated by: Prof. Evelien Dekker, MD, PhD, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

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

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 Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

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.

Nature and extent of the burden and risks associated with participation, benefit and group relatedness: At baseline and at three monthly visits a medical history will be taken and physical examinations will be performed, as well as laboratory tests and HRQoL questionnaires. Trough level testing of sirolimus will be measured at day 7 after start of the study drug and weekly until the therapeutic range has been achieved, after which the next trough level will be measured at 3 and 6 months follow-up. Finally, monthly telephone check-ups will be carried out. LGI endoscopies will be done at baseline and at 6 months. For this study, patients are included with severe rectal or pouch polyposis as they are expected to have an indication for invasive surgery on a short-term base and no other less invasive alternative therapy is available.

Study Type

Interventional

Enrollment (Actual)

4

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Netherlands
    • Noord-Holland
      • Amsterdam, Noord-Holland, Netherlands, 1105AZ
        • Academic Medical Centre

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • ≥ 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

Exclusion Criteria:

  • 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)

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Sirolimus
All patients will receive sirolimus for the duration of the study, with a trough level target range of 5-8 ng/ml.
Drug: Sirolimus
Participants will be given sirolimus tablets. The starting dose is 2 mg once daily which will be given in 1mg tablets. On day 7 the first trough level is measured (using the LC-MS/MS method) and if not within the target range of 5-8ng/ml, dosing adjustments are made. In case of dosing adjustments, the next trough level is measured seven days later and this is repeated weekly until the target range is achieved. In case trough levels are within the target range, the next trough level measurement is at month 3, after which dosing adjustments are made if necessary, and at month 6. The maximum daily dose is 40mg. No placebo is given.
Other Names:
  • Rapamune

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change in Marked Polyp Size
Time Frame: 6 Months
Effect of sirolimus on the size of 5 marked polyps per patient based on video observations.
6 Months
Median Number of Treatment-Related Adverse Events Per Participant
Time Frame: 6 Months
Summary analysis of adverse events, clinical laboratory abnormalities and regular physical examination.
6 Months

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.
6 Months
Median Difference in Number of Intestinal Polyps
Time Frame: 6 Months
Number of intestinal polyps was determined by two independent reviewers, blinded for the order of videos (before and after treatment). The median difference comparing baseline en after 6 months of treatment was reported.
6 Months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

Investigators

  • Principal Investigator: Evelien Dekker, MD, PhD, Academic Medical Centre Amsterdam

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

October 3, 2017

Primary Completion (Actual)

December 10, 2018

Study Completion (Actual)

December 10, 2018

Study Registration Dates

First Submitted

March 21, 2017

First Submitted That Met QC Criteria

March 24, 2017

First Posted (Actual)

March 30, 2017

Study Record Updates

Last Update Posted (Actual)

October 24, 2024

Last Update Submitted That Met QC Criteria

August 2, 2024

Last Verified

August 1, 2024

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • NL55868.018.15

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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