Sirolimus for the treatment of severe intestinal polyposis in patients with familial adenomatous polyposis (FAP); a pilot study

Recruitment & Eligibility

Status: Completed

Sex: Not specified

Target Recruitment: 5

Inclusion Criteria

- >= 18 years
-A genetically confirmed APC mutation
-Classical FAP phenotype (100-1000 colorectal adenomatous polyps)
-Subtotal colectomy with ileorectal anastomosis (IRA) or ileo-anal pouch anastomosis
-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 treatment

Exclusion Criteria

-Inability to give informed consent
-Participation in another interventional clinical trial
-Subjects who are pregnant or breast-feeding
-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
-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 its excipients or drugs of similar chemical classes
-Regular NSAID use
-Use of other FAP directed drug therapies
-Subjects requiring systemic anticoagulation
-Co-medication that could interact with sirolimus: Ciclosporine, IL-2-receptorantibodies, Calcineurine inhibitors, HMG-CoA-reductase inhibitors, fibrates, CYP3A4-inhibitors (such as ketoconazol, voriconazol, itraconazol, telitromycine, claritromycine, troleandomycine, verapamil, diltiazem, erytromycine, ritonavir, indinavir, boceprevir, telapravir, nicardipine, bromocriptine, cimetidine, danazol), CYP3A4-inductors (such as rifampicine, rifabutine, St. Janskruid, carbamazepine, fenobarbital, fenytoine), ACE-inhibitors, cisapride, metoclopramide), Pgp inhibitors
-Use of grapefruit juice
-Use of attenuated vaccins;-Significant abnormalities in hepatic function
-Significant hematologic abnormalities
-Increased fasting serum cholesterol or triglyceride (whether or not on lipid-lowering therapy)
-Increased glucose
-Electrolyte abnormalities
-Calculated glomerular filtration rate (GFR) less than 40 mL/min/1.73m2
using the simplified Modification of Diet in Renal Disease (MDRD) formula
-Spot urine protein to creatinine ratio (UPr/Cr) greater than or equal to 0.5

Study & Design

Study Type: Interventional

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
<p>• Size of 5 marked polyps 5 patients with FAP and a large intestinal polyp<br /><br>burden<br /><br>• Safety outcomes reported by summary analysis of adverse events , clinical<br /><br>laboratory abnormalities and regular physical examination</p><br>

Secondary Outcome Measures

Name	Time	Method
<p>• Number of polyps<br /><br>• Global polyp burden<br /><br>• Histology (tubular, tubulovillous or villous histology and degree of<br /><br>dysplasia)<br /><br>• Patient reported quality of life using HRQoL questionnaires<br /><br>• Rate of cell proliferation in healthy intestinal mucosa and adenomatous tissue<br /><br>• Immunohistochemistry of mTOR targets (such as eEF2 kinase, phospho-S6) in<br /><br>healthy intestinal mucosa and adenomatous tissue</p><br>

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