DFMO/SULINDAC PHASE III

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. OBJECTIVES Adenomatous polyps are generally regarded as precursors to colorectal cancer and relatively late surrogates in the carcinogenic pathway to the development of these malignancies. Etiologic and experimental investigations have established the critical nature of definable molecular changes precedent to and during pathogenesis of the disease that leads to abnormal signaling pathways and defective growth control. Extensive epidemiologic studies have identified numerous dietary and non-dietary factors that affect adenoma and colorectal cancer development, including regular intake of non-steriodal anti-inflammatory drugs (NSAIDs). Experimental interventions in several animal models have demonstrated that NSAIDs as well as the polyamine synthesis inhibitor, difluoromethylornithine (DFMO), inhibit carcinogenesis including adenoma formation and colon cancer. We and others have performed Phase I, IIa and IIb clinical chemoprevention trials of DFMO and in a series of studies that have established its effectiveness in lowering the polyamine content of colorectal tissue at doses of DFMO that are almost completely free of side effects. The NSAID and sulindac has been shown to cause regression of FAP and sporadic associated polyps and its side effects profile is widely understood. The available data on these two agents and their potential role as candidate preventive agents for colorectal cancer is as comprehensive as for any agent(s) currently being considered for human use and they represent the intervention focus of this proposal. We have nearly completed accrual to our Phase IIb combination trial fo DFMO plus sulindac versus placebo in which the major goal was to study various pathobiologic markers in flat mucosa and incident adenoma recurrence. We propose to use this large group of individuals as a Vanguard for a randomized, placebo-controlled, phase III trial of DFMO plus sulindac to determine whether this combination can decrease substantially the recurrence of adenomatous polyps and do so safely. SPECIFIC AIMS 1. To conduct a randomized, double-blind, placebo-controlled phase III clinical chemoprevention trial of the combination of DFMO plus sulindac to decrease the rate of new adenomatous polyp formation. Hypothesis: This combination of candidate chemoprevention agents will lower the rate of adenomatous polyps by 50% or greater. Qualifying and recurrent adenomas will be collected, measured, and archived for future studies. Dietary parameters will be measured and family history of colorectal cancer and polyps will be determined in all randomized participants. 2. To correlate the effects of the combination on polyamine and prostaglandin contents in the flat mucosa to the rate of adenoma formation. The changes in the levels fo these biochemical parameters will also be used as one measure of compliance as well as an indication that the agent is producing the intended biochemical modulation. Hypothesis: The level of reduction of polyamine and prostaglandin contents of flat mucosa after 36 months of treatment will be correlated with the rate of adenoma recurrence. 3. To determine the side effects in patients randomized to the combination therapy over the course of the intervention. Hypothesis: Both GI and non-GI side effects, as well as drop-offs after randomization, will be no different between the treatment and placebo arms. The major objectives of this investigation are to reduce the recurrence rate of adenomatous colonic polyps without producing toxicity greater than seen in the placebo group. The overall goal of our work is to develop safe combinations of chemoprevention agents that can be used in the practice setting and complement current surveillance efforts.