P-305 A Phase Ib Biomarker Trial of Naproxen in Patients at Risk for DNA Mismatch Repair Deficient Colorectal Cancer

Abstract

Introduction: Background: Approximately 15% of colorectal cancers (CRC) display Microsatellite Instability (MSI) due to deficient functioning of the DNA mismatch repair (MMR) system. The origin of this deficiency is either genetic due to mutations in the MMR genes MLH1, MSH2/TACSTD1, MSH6 and PMS2 or sporadic due to hypermethylation of the promoter of the MLH1 gene (sporadic MSI). Patients diagnosed with germline mutations in MMR genes (Lynch Syndrome, LS) have an up to 70-80% lifetime risk of CRC and have the potential to benefit from effective chemopreventive strategies. In fact, the CAPP-II trial demonstrated that aspirin decreased incidence of tumors associated with LS, but barriers to its adoption are the large doses needed and the potential side effects. Use of other non-steroidal anti-inflammatory drugs (NSAID) with stronger efficacy and better tolerability may represent novel strategies for chemoprevention. Naproxen is a NSAID that is widely used with an excellent safety profile. In addition, a recent pre-clinical study sponsored by the Division of Cancer Prevention of the National Cancer Institute using a genetically engineered mouse model of Lynch Syndrome (VC-MSH2-LoxP) has shown that Naproxen is the most effective agent from a panel of NSAIDs in preventing CRC. The present clinical trial was designed to confirm, in human subjects with LS, the biomarker modulation and tolerability of Naproxen that has been observed in preclinical animal models. We report herein the background, schema and early recruitment efforts of this randomized, placebo-controlled trial. Methods: Trial design: The eligible patient cohort includes individuals who carry a pathogenic germline mutation in one of the MMR genes (LS) and individuals who have been diagnosed with non-sporadic MSI-high tumors [i.e. no evidence of MLH1 hypermethylation or BRAF mutation, Lynch-Like Syndrome patients (LLS)]. 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. Response to treatment will be defined as having a 30% reduction in the PGE2 level in post-treatment (compared with pre-treatment) colorectal biopsies. The study is being conducted at 3 clinical sites (The University of Texas MD Anderson Cancer Center, The University of Michigan Comprehensive Cancer Center and Dana Farber Cancer Institute). This trial was activated in January of 2014 and as of December 2014 a total of 20 subjects (18 with LS and 2 with LLS) were accrued. Thirteen are female and 7 are male. Ninety percent of subjects are Caucasian. Sixteen subjects are currently evaluable for efficacy and all are evaluable for toxicity. The treatment has been well tolerated with the majority of adverse events being grade 1-2. Two patients experienced unrelated grade 3 events.