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Sirolimus and Familial Adenomatous Polyposis (FAP)

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ClinicalTrials.gov Identifier: NCT03095703
Recruitment Status : Completed
First Posted : March 30, 2017
Last Update Posted : January 28, 2019
Sponsor:
Information provided by (Responsible Party):
Prof. Evelien Dekker, MD, PhD, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

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.

Condition or disease Intervention/treatment Phase
Adenomatous Polyposis Coli Drug: Sirolimus Phase 2

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.


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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 4 participants
Intervention Model: Single Group Assignment
Intervention Model Description: A Prospective phase II pilot study with 5 patients with a follow-up of 6 months.
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Sirolimus for the Treatment of Severe Intestinal Polyposis in Patients With Familial Adenomatous Polyposis (FAP): a Pilot Study
Actual Study Start Date : October 3, 2017
Actual Primary Completion Date : December 10, 2018
Actual Study Completion Date : December 10, 2018


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 Name: Rapamune




Primary Outcome Measures :
  1. Size of intestinal polyps [ Time Frame: 6 Months ]
    Effect of sirolimus on the size of 5 marked polyps

  2. Number of participants with treatment-related adverse events [ Time Frame: 6 Months ]
    Summary analysis of adverse events, clinical laboratory abnormalities and regular physical examination.


Secondary Outcome Measures :
  1. 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.

  2. 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.

  3. Histology of intestinal polyps [ Time Frame: 6 Months ]
    Histology will be reported as tubular, tubulovillous or villous with'the degree of dysplasia.

  4. Patient reported quality of life [ Time Frame: 6 Months ]
    Patient reported quality of life using HRQoL questionnaires

  5. Rate of cell proliferation [ Time Frame: 6 Months ]
    Rate of cell proliferation in healthy intestinal mucosa and adenomatous tissue

  6. 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



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03095703


Locations
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Netherlands
Academic Medical Centre
Amsterdam, Noord-Holland, Netherlands, 1105AZ
Sponsors and Collaborators
Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Investigators
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Principal Investigator: Evelien Dekker, MD, PhD Academic Medical Centre Amsterdam

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Responsible Party: Prof. Evelien Dekker, MD, PhD, Professor MD, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
ClinicalTrials.gov Identifier: NCT03095703     History of Changes
Other Study ID Numbers: NL55868.018.15
First Posted: March 30, 2017    Key Record Dates
Last Update Posted: January 28, 2019
Last Verified: January 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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

Keywords provided by Prof. Evelien Dekker, MD, PhD, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA):
Sirolimus
Intestinal adenomas

Additional relevant MeSH terms:
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Colorectal Neoplasms
Nasopharyngeal Neoplasms
Adenomatous Polyposis Coli
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases
Pharyngeal Neoplasms
Otorhinolaryngologic Neoplasms
Head and Neck Neoplasms
Nasopharyngeal Diseases
Pharyngeal Diseases
Stomatognathic Diseases
Otorhinolaryngologic Diseases
Adenomatous Polyps
Adenoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplastic Syndromes, Hereditary
Intestinal Polyposis
Genetic Diseases, Inborn
Sirolimus
Everolimus
Anti-Bacterial Agents