Abstract C52: A phase Ib biomarker trial of naproxen in patients at risk for DNA mismatch repair deficient colorectal cancer

Rationale: Approximately 15% of colorectal cancers (CRC) display Microsatellite Instability (MSI). The DNA mismatch repair (MMR) system is deficient in this tumor subtype secondary to a germline mutation in one of the MMR system genes (MLH1, MSH2, MSH6, PMS2) or to the presence of hypermethylation MLH1. Therefore, MSI tumors can have a genetic origin (Lynch syndrome) or a sporadic origin (hypermethylated MSI tumors). Patients and families diagnosed with Lynch Syndrome have an up to 70-80% lifetime risk of CRC. Therefore, this high-risk population may benefit from effective chemopreventive strategies. Results from the CAPP-II trial suggest that aspirin use is associated with reduction of risk for CRC and other tumors in Lynch syndrome; however the large doses needed and potential side effects present barriers to adoption. Other non-steroidal anti-inflammatory drugs (NSAID) with stronger efficacy and better tolerability may be reasonable alternatives for CRC chemoprevention. Naproxen is a NSAID that is widely used in the community with an excellent safety profile. Recent pre-clinical data sponsored by the Division of Cancer Prevention of the National Cancer Institute using a conditional mouse model of Lynch Syndrome (VC-MSH2-LoxP) have shown that Naproxen is the most effective agent from a panel of NSAIDs preventing CRC. Therefore, this clinical trial was designed to confirm the activity of Naproxen observed in vivo in patients diagnosed with Lynch Syndrome. Because NSAIDs exert their therapeutic effects through the inhibition of COX-1/-2 which in turn leads to a reduction in prostaglandin production, tissue level of prostaglandin E2 (PGE2) is a robust biomarker for the effect of NSAIDs. We wish to report herein the background and schema of this early-phase (Ib) cancer prevention trial to introduce the concept of NSAID chemoprevention strategy in this specialized and genetically well-defined patient population, and thus to also facilitate the identification of additional collaborators for potential further larger trials initiatives. Design: Eligible patients include individuals harboring a pathogenic mutation in one of the MMR genes and individuals who have been diagnosed with non-sporadic MSI-high tumors (i.e. no evidence of MLH1 hypermethylation or BRAF mutation). The primary endpoints are to test whether Naproxen at a once-daily 220 mg (low-) or 440 mg (high-) dose, administered for 6 months, reduces the concentration of PGE2 levels in normal colorectal mucosa, when compared to placebo; and to determine the safety profile and tolerability of Naproxen. A total of 60 participants will be randomized to achieve an evaluable sample size of 45 participants. Under the assumption of an effect size of 1.25, we will have 80% power for pairwise comparisons by the two-sample t-test among the three groups with 15 evaluable participants per group. Response to treatment will be defined as having a 30% reduction in the PGE2 level post-treatment. Secondary endpoints include the determination of Naproxen concentrations in plasma and in normal colorectal mucosa after 6 months of treatment, and levels of PGE2 in urine after 6 months of treatment, all measured by validated biomarker assays. The study will be conducted at three clinical sites (The University of Texas MD Anderson Cancer Center, The University of Michigan Comprehensive Cancer Center and Dana Farber Cancer Institute). Screening and accrual are expected to begin in the latter part of 2013. Supported by NCI, DCP Contract HHSN261201200034I to the UT MD Anderson Cancer Prevention Agent Development Program: Early Phase Clinical Research Consortium. Citation Format: Eduardo Vilar, Y. Nancy You, Lana A. Vornik, Elena M. Stoffel, Ramona M. Lim, Steven M. Lipkin, Marjorie Perloff, Powel H. Brown. A phase Ib biomarker trial of naproxen in patients at risk for DNA mismatch repair deficient colorectal cancer. [abstract]. In: Proceedings of the Twelfth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2013 Oct 27-30; National Harbor, MD. Philadelphia (PA): AACR; Can Prev Res 2013;6(11 Suppl): Abstract nr C52.