Naproxen in Preventing DNA Mismatch Repair Deficient Colorectal Cancer in Patients With Lynch Syndrome

PRIMARY OBJECTIVES:

I. To determine whether treatment with naproxen at a once-daily 220 mg or 440-mg dose,
administered for 6 months as compared to placebo reduces the concentration of prostaglandin
E2 (PGE2) levels in normal colorectal mucosa in subjects at risk for a mismatch repair
deficient colorectal cancer.

II. To determine the toxicity profile and tolerability of naproxen at two doses (220 mg or
440-mg once daily) as compared to placebo over 6 months of therapy in subjects at risk for a
mismatch repair deficient colorectal cancer.

SECONDARY OBJECTIVES:

I. To determine naproxen concentrations in plasma of patients at risk for DNA mismatch repair
deficient colorectal cancer taking naproxen once daily, 220 mg, 440 mg or placebo after 6
months of therapy compared to baseline levels.

II. To determine naproxen concentrations in normal colorectal mucosa of patients at risk for
DNA mismatch repair deficient colorectal cancers (CRC) taking naproxen once daily 220 mg, 440
mg or placebo after 6 months of therapy compared to baseline levels.

III. To determine whether urinary prostaglandin-endoperoxide synthase 1 metabolite (PGE-M) is
significantly higher in patients at risk for DNA mismatch repair deficient CRC taking
naproxen one daily, 220 mg, 440 mg or placebo after 6 months of therapy compared to baseline
levels.

IV. To determine whether 6-months therapy with naproxen once daily, 220 mg, 440 mg or placebo
leads to a reduction in the number of polyps observed in the rectosigmoid and rectal area.

V. To determine whether naproxen once daily, 220 mg, 440 mg or placebo will significantly
change the micro-ribonucleic (RNA) profile of normal colorectal mucosa in patients at risk
for DNA mismatch repair deficient CRC compared to the baseline.

VI. To determine whether naproxen once daily, 220 mg, 440 mg or placebo will significantly
change the gene expression messenger RNA (mRNA) profile of normal colorectal mucosa in
patients at risk for DNA mismatch repair deficient CRC compared to the baseline.

VII. To determine whether naproxen once daily, 220 mg, 440 mg or placebo will significantly
change the mutational rate in patients at risk for DNA mismatch repair deficient CRC compared
to placebo.

VIII. To determine future candidate biomarkers measured by genomic and transcriptomic
platforms in tissue biopsies of normal colorectal mucosa in individuals at risk for mismatch
repair deficient CRC pre- and post-treatment with naproxen.

IX. To determine whether Naproxen once daily, 220 mg, 440 mg or placebo will significantly
change the microbiome profile of normal colorectal mucosa in patients at risk for DNA
mismatch repair deficient CRC compared to the baseline.

X. To determine whether treatment with Naproxen once daily, 220 mg, 440 mg after 6 months of
therapy as compared to placebo changed PGF2, PGD2, Thromboxane B2, 9a11b-PGF2a and
6-KetoPGF1a levels in colorectal mucosa of subjects at risk for a mismatch repair deficient
colorectal cancer.

XI. To determine whether treatment with Naproxen once daily, 220 mg, 440 mg after 6 months of
therapy as compared to placebo changed the number of stem cells and induced differentiation
into other cell lineages in colorectal mucosa of subjects at risk for mismatch repair
deficient colorectal cancer.

OUTLINE: Patients are randomized to 1 of 3 treatment arms.

ARM I: Patients receive high-dose naproxen orally (PO) once daily (QD) for 6 months.

ARM II: Patients receive low-dose naproxen PO QD and placebo PO QD for 6 months.

ARM III: Patients receive placebo PO QD for 6 months.

After completion of study treatment, patients are followed up for 2 weeks.

Inclusion Criteria:

- Participants must have Lynch syndrome defined as meeting any of the following:

- "Mutation-positive Lynch syndrome": carriers or obligate carriers (by pedigree)
of a pathogenic mutation in one of the DNA mismatch repair (MMR) genes (i.e. mutL
homolog 1 [MLH1], mutS homolog 2 [MSH2]/epithelial cell adhesion molecule
[EPCAM], mutS homolog 6 [MSH6], or PMS2 postmeiotic segregation increased 2 [S.
cerevisiae] [PMS2]) or

- "Mutation-negative Lynch syndrome": patients with a personal history of a
non-sporadic MMR deficient premalignant lesion (i.e. polyp) or a non-sporadic MMR
deficient malignant tumor (where "non-sporadic MMR deficient" is defined by:
microsatellite-instability high by either immunohistochemistry or microsatellite
instability [MSI] testing or both, but no evidence of MLH1 promoter methylation
in cases with loss of both MLH1 and PMS2, and/or no evidence of v-raf murine
sarcoma viral oncogene homolog B [BRAF] mutation in cases with loss of both MLH1
and PMS2) but germline MMR genetic testing showed either a variant of unknown
significance or mutation negative result or had declined germline MMR genetic
testing

- Participants must not have evidence of active/recurrent malignant disease for 6 months

- Participants must be at least 6 months from any prior cancer-directed treatment (such
as surgical resection, chemotherapy, immunotherapy, hormonal therapy or radiation)

- Participants must have endoscopically accessible distal colon and/or rectal mucosa
(i.e. participants must have at least part of the descending/sigmoid colon and/or
rectum intact)

- Participants must consent to one standard of care lower gastrointestinal (GI)
endoscopy (flexible sigmoidoscopy or colonoscopy) with biopsies and one flexible
sigmoidoscopy with biopsies that will be 6 months (+14 days) apart

- Participants must consent to refrain from using aspirin or non-steroidal
anti-inflammatory drugs (NSAIDs) or cyclooxygenase (COX)-inhibitors for the duration
of the trial

- Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 70%)

- Hemoglobin >= 10 g/dL or hematocrit >= 30%

- Leukocyte count >= 3,000/microliter

- Platelet count >= 100,000/microliter

- Absolute neutrophil count >= 1,500/microliter

- Creatinine =< 1.5 x institutional upper limit of normal (ULN) (OR glomerular
filtration rate [GFR] > 30 ml/min/1.73 m^2)

- Total bilirubin =< 2 x institutional ULN

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) =<
2.5 × institutional ULN

- Alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 ×
institutional ULN

- Women of child-bearing potential must agree to use adequate contraception (hormonal or
barrier method of birth control; abstinence) for the duration of study participation;
should a woman become pregnant or suspect she is pregnant at the time of study entry
or while participating in this study, she should inform her study physician
immediately; women of childbearing potential must agree to baseline and pre-drug
pregnancy tests

- Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

- Individuals who received scheduled aspirin, NSAIDs, or COX-inhibitors of any kind for
more than 3 days (> 3 days) during anytime within the 2 weeks preceding baseline
eligibility screening visit; individuals on cardio-protective aspirin will not be
eligible

- Individuals who are status post total proctocolectomy (i.e. removal of all colon and
rectum)

- Individuals with active gastroduodenal ulcer disease in the preceding 5 years

- Individuals with any history of transfusion-dependent gastrointestinal bleeding,
gastrointestinal perforation or gastrointestinal obstruction; if any of these events
had been due to a malignancy of the GI tract and the malignancy has since been
removed, the patient is eligible

- Individuals with history of myocardial infarction, stroke, coronary-artery bypass
draft, invasive coronary revascularization in the preceding 5 years

- Individuals taking the drugs listed below may not be randomized unless they are
willing to stop the medications (and possibly change to alternative non-excluded
medications to treat the same conditions) no less than 7 days prior to starting
naproxen or placebo on this study; consultation with the participant's primary care
provider may be obtained but is not required; the use of the following drugs or drug
classes is prohibited during naproxen/placebo treatment:

- Investigational agents

- NSAIDs: such as aspirin, ketorolac and others NSAIDs

- COX-2 inhibitors: such as celecoxib, rofecoxib and other COX-2

- Antiplatelet agents: such as aspirin, clopidogrel, ticlopidine, dipyridamole,
abciximab, tirofiban, eptifibatide and prasugrel

- Anticoagulants:

- Heparin

- Heparinoids: such as fondaparinux, danaparoid and other heparinoids

- Low-molecular weight heparins: such as enoxaparin, dalteparin, parnaparin,
reviparin, tinzaparin, ardeparin, certoparin, lepirudin, bivalirudin

- Other anticoagulants: argatroban, apixaban, dabigatran, rivaroxaban,
warfarin, acenocoumarol, dicumarol, phenindione and other anticoagulants

- Lithium

- Selective serotonin and norepinephrine reuptake inhibitors: milnacipran,
fluoxetine, paroxetine, nefazodone, citalopram, clovoxamine, escitalopram,
flesinoxan, femoxetine, duloxetine, venlafaxine, vilazodone, sibutramine,
desvenlafaxine

- Anticonvulsants: phenytoin, paraldehyde, valproic acid, carbamazepine,
trimethadione, phenobarbital, diazepam, chlormethiazole, mephenytoin, ethotoin,
paramethadione, phenacemide, mephobarbital, oxcarbazepine, zonisamide, piracetam,
vigabatrin, felbamate, gabapentin, beclamide, fosphenytoin, stiripentol,
tiagabine, topiramate, pregabalin, lacosamide, rufinamide, caramiphen

- Antibiotics and antifungals:

- Fluoroquinolones : such as ofloxacin, norfloxacin, levofloxacin

- Other agents: teriflunomide, cyclosporine, tacrolimus, ginkgo, gossypol,
meadowsweet, feverfew, beta glucan, pentosan, pentoxifylline, cilostazol,
erlotinib, pemetrexed, methotrexate, pralatrexate

- Individuals with uncontrolled renal insufficiency or renal failure

- History of allergic reactions attributed to naproxen

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, uncontrolled hypertension, symptomatic congestive heart failure, unstable
angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that
would limit compliance with study requirements

- Pregnant, breast-feeding, or women of childbearing potential unwilling to use a
reliable contraceptive method; pregnant women are excluded from this study;
breastfeeding should be discontinued if the mother is treated with naproxen