The aim of our 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.
ID
Source
Brief title
Condition
- Benign neoplasms gastrointestinal
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
• Size of 5 marked polyps 5 patients with FAP and a large intestinal polyp
burden
• Safety outcomes reported by summary analysis of adverse events , clinical
laboratory abnormalities and regular physical examination
Secondary outcome
• Number of polyps
• Global polyp burden
• Histology (tubular, tubulovillous or villous histology and degree of
dysplasia)
• Patient reported quality of life using HRQoL questionnaires
• Rate of cell proliferation in healthy intestinal mucosa and adenomatous tissue
• Immunohistochemistry of mTOR targets (such as eEF2 kinase, phospho-S6) in
healthy intestinal mucosa and adenomatous tissue
Background summary
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 39 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. We
hypothesize that sirolimus could lead to regression of intestinal polyps in
patients with FAP.
Study objective
The aim of our 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
This is a prospective phase II pilot study that will take place at the Academic
Medical Center (AMC). Five patients with FAP will be invited for study
participation. The total study duration will be 6 months. At baseline and at 6
months follow-up all included patients will undergo a lower gastrointestinal
(LGI) endoscopy. Safety outcomes will be assessed by laboratory tests, physical
examinations and telephone check-ups. Sirolimus trough levels will be measured
regularly and if needed dosing adjustments will be made.
Intervention
All patients will receive sirolimus for the duration of the study (6 months),
with a trough level target range of 5-8 ng/ml.
Study burden and risks
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, we
include patients with severe intestinal polyposis as they are expected to have
an indication for invasive surgery on a short-term and no other less invasive
alternative therapy is available.
The use of sirolimus is associated with a risk of several side-effects. By
frequent telephone contact, lab testing, physical examination and trough level
testing, side-effects can be identified on a short term base and if indicated
they can be treated or surveilled. The relatively short study duration and low
dosing of sirolimus minimize the chance of developing side-effects.
Meibergdreef 9
Amsterdam 1105 AZ
NL
Meibergdreef 9
Amsterdam 1105 AZ
NL
Listed location countries
Age
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
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2015-005527-12-NL |
| CCMO | NL55868.018.15 |