Adenomatous Polyposis Coli
Conditions
Keywords
Sirolimus, Intestinal adenomas
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 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.
Interventions
DRUGSirolimus
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.
Sponsors
Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
A Prospective phase II pilot study with 5 patients with a follow-up of 6 months.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Median Number of Treatment-Related Adverse Events Per Participant | 6 Months | Summary analysis of adverse events, clinical laboratory abnormalities and regular physical examination. |
| Change in Marked Polyp Size | 6 Months | Effect of sirolimus on the size of 5 marked polyps per patient based on video observations. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Median Difference in Number of Intestinal Polyps | 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. |
| Global Polyp Burden | 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. |
Countries
Netherlands
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Sirolimus All patients will receive sirolimus for the duration of the study, with a trough level target range of 5-8 ng/ml.
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. | 4 |
| Total | 4 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Sirolimus |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 4 Participants |
| Age, Continuous | 50 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 4 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 4 Participants |
| Region of Enrollment Netherlands | 4 participants |
| Sex: Female, Male Female | 2 Participants |
| Sex: Female, Male Male | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 4 |
| other Total, other adverse events | 4 / 4 |
| serious Total, serious adverse events | 1 / 4 |
Outcome results
Primary
Change in Marked Polyp Size
Effect of sirolimus on the size of 5 marked polyps per patient based on video observations.
Time frame: 6 Months
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Sirolimus | Change in Marked Polyp Size | Decrease in marked polyp size | 16 Size of marked polyps |
| Sirolimus | Change in Marked Polyp Size | Same marked polyp size | 4 Size of marked polyps |
| Sirolimus | Change in Marked Polyp Size | Increase in marked polyp size | 0 Size of marked polyps |
Primary
Median Number of Treatment-Related Adverse Events Per Participant
Summary analysis of adverse events, clinical laboratory abnormalities and regular physical examination.
Time frame: 6 Months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Sirolimus | Median Number of Treatment-Related Adverse Events Per Participant | 10 Number of Adverse Events |
Secondary
Global Polyp Burden
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.
Time frame: 6 Months
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Sirolimus | Global Polyp Burden | Much better | 0 Participants |
| Sirolimus | Global Polyp Burden | Better | 3 Participants |
| Sirolimus | Global Polyp Burden | Same | 1 Participants |
| Sirolimus | Global Polyp Burden | Worse | 0 Participants |
| Sirolimus | Global Polyp Burden | Much worse | 0 Participants |
Secondary
Median Difference in Number of Intestinal Polyps
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.
Time frame: 6 Months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Sirolimus | Median Difference in Number of Intestinal Polyps | 25.75 Median number of polyps |