Mesalamine for Colorectal Cancer Prevention Program in Lynch syndrome

Colorectaal cancer (CRC) has become the second leading cause of cancer death
for both females and males. Individuals with Lynch syndrome (LS) live under
constant threat of cancer development throughout adulthood. LS individuals here
are defined as carriers of a deleterious mismatch repair (MMR) gene mutation in
MLH1, MSH2, MSH6, or PMS2, have a 50%-80% lifetime risk for the development of
CRC (colorectal cancer). The prevalence of LS in colorectal and endometrial
cancer patients is about 1-4% [1, 2]. On extrapolation to the entire
population, the incidence of LS is estimated between 1:2000 and 1:660. There
are even higher estimates that the population incidence of LS is approximately
1 in 370 [3]. Thus, over a quarter- to one million individuals may be affected
within the European Union [1]. Chemoprevention is a big hope for LS family
members.

Cancer prevention in LS has been studied in the past. The CaPP2 trial has
tested the effect of 600mg aspirin in a large multinational cohort and showed
no benefit for its primary outcome [20]. A secondary post-hoc analysis
demonstrated a statistical significant effect as a delayed response [21]
leaving the problem unanswered [22]. Since 600mg of aspirin are difficult to
tolerate for longer periods and the chemopreventive effect may be just as high
with a lower dosage, the authors of CaPP2 have initiated a follow-up trial to
compare lower doses of aspirin with 600mg (CaPP3; communication John Burn).

Cancer development in LS occurs through a mutational mechanism called
microsatellite instability (MSI). One way to interfere with cancer
development in LS is to improve replication fidelity and thereby reduce the
speed of MSI. In vitro, mesalamine (5-ASA), a well-tolerated drug that had been
used for over 30 years in ulcerative colitis, reduces MSI via improvement
of replication fidelity [5]. 5-ASA activates a replication checkpoint
thereby allowing more time for cells to pass through S-phase leading to less
replications errors [6]. This effect of 5-ASA is specific for the position of
the amino group [7], as 3 ASA or 4-ASA had no such effect, and applicable for
various repetitive sequences such as mono- (including TGFBR2 and ACVR2), di-
and tetranucleotide repeats [8]. In Msh2 loxP/loxP Villin-Cre mice [9],
which best resemble LS of the intestine, 5-ASA reduces tumor incidence,
multiplicity and reduces the number of mutations in five selected
microsatellite repeats in the normal mucosa [10]. Such a chemopreventive
effect was not observed upon aspirin [11], which has no effect on MSI either
[5]. 5-ASA has minimal toxicity as it is delivered to the colon
through slow release formulations and immediately inactivated
(N-acetylated) within the colonic mucosa. The drug is not systemically
active. Thereby it would fulfill all requirements for a designer
drug for CRC prevention in LS. In addition epidemiological data
support its chemopreventive properties in humans as it reduces the
risk of CRC in patients with ulcerative colitis [12]. However, so far it is
unclear whether such effect is mediated through its anti-inflammatory or
various anti-neoplastic properties [13]

Primairy Objective
* To test whether 5-ASA reduces the occurrence of colonic benign or
malignant neoplasia compared to placebo in Lynch syndrome (LS) patients
as detected by any colonoscopy until the end of study.

Secondary Objectives
* To test wheter 5-ASA reduces the number of neoplasms (tumor multiplicity) and
tumor progression to placebo in LS patients at the end of the study.
Advanced adenomas are defined by a diameter above 1 cm villous or tubulu
villous histology or high grade dysplasia.
* To investigate if differences between 5-ASA effects and placebo
effects on the occurrence of colonic neoplasia, tumor multiplicity or tumor
progression depend on the history of
colorectal cancer, sex and patients age (LS patients below 45 years of age or
45 years of age and older).
* To investigate differences between low and high dose 5-ASA with
respect to the occurrence of colonic neoplasia, to tumor multiplicity and tumor
progression.

Multicenter, multinational, randomized, 3-arm, double-blind, phase II
clinical study with 2400mg 5-ASA, 1200mg 5-ASA or placebo in LS
patients for 2 years.

screening visit: laboratory examinations (hematology, serum chemistry,
creatinine, amylase and lipase), pregnancy test, colonoscopy, (colonoscopy is
standard test) serum and stool. Total amount of blood collection is 16 ml.

randomization visit/control visits: creatinine, amylase and lipase. Total
amount of blood collection is 6 ml.

1 year control visits: creatinine, amylase and lipase, colonoscopy,
(colonoscopy only if patient is used to have a yearly colonoscopy). Total
amount of blood collection is 6 ml.

end of study visit: laboratory examinations (hematology, serum chemistry,
creatinine, amylase and lipase), pregnancy test, colonoscopy, (colonoscopy is
standard test) serum and stool. Total amount of blood collection is 16 ml.

Load
There are no expected impacts or restrictions on the lifestyle of the patient.
The patient should take 2 tablets once daily in the morning and write them down
in his patient diary. Every 5-7 weeks between two visits, the patient receives
a call from his study doctor or study staff. The patient should visit the
hospital every three months. It is important that the patient goes to the
scheduled visits and that the planned study procedures and tests are performed.
It is also important that the patient takes the study medication as prescribed
and the patient writes down the study medication intake in his patients diary.
The patient should return all unused study medication and all containers (even
empty containers) at the first next visit in the hospital. It is also important
that the patient informs the study team about any other medications that he has
used before and during the study. Because some drugs are not permitted during
the study, the patient should first discuss the planned treatment with his
study doctor before starting to use the drug.

Risk
Mesalamine is a very well-tolerated. As every medication, the treatment with
Mesalamine can induce possible side effects or other disorders. Known side
effects include soft stool, outright diarrhea, abdominal discomfort, nausea,
flatulence, and less common headache and rash or other hypersensitivity
reactions. Blood sampling can cause pain, bruising and light headedness.