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

Lynch Syndrome Clinical Trial

Official title: A Phase Ib Biomarker Trial of Naproxen in Patients at Risk for DNA Mismatch Repair Deficient Colorectal Cancer

Status Completed

Clinical Trial Summary

This randomized phase Ib trial studies the side effects and best dose of naproxen in preventing deoxyribonucleic acid (DNA) mismatch repair deficient colorectal cancer in patients with Lynch syndrome. Chemoprevention is the use of certain drugs to keep cancer from forming. The use of naproxen may keep cancer from forming in patients with Lynch syndrome.

Clinical Trial Description

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.

XII. 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 immune and mesenchymal cells recruited to the 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. ;

Related Conditions & MeSH terms

• Colorectal Neoplasms, Hereditary Nonpolyposis
• Lynch Syndrome
• Syndrome

• NCT number: NCT02052908
• Study type: Interventional
• Source: National Cancer Institute (NCI)
• Status: Completed
• Phase: Phase 1
• Start date: January 27, 2014
• Completion date: January 5, 2021