CONTEXT Carcinoid syndrome (CS) is associated with elevated serotonin, diarrhea, flushing, and increased risk of valvular heart disease. Many patients respond to somatostatin analogs initially, but response diminishes in most patients. Additional options are needed. OBJECTIVE To assess whether telotristat etiprate (TE) can reduce gastrointestinal symptoms in CS and reduce urinary 5-hydroxyindoleacetic acid (u5-HIAA; a biomarker of serotonin). DESIGN A prospective, exploratory, dose-escalating 12-week, open-label, multicenter study of TE with efficacy and safety analyses. SETTING A multicenter study. PATIENTS Eligible patients had metastatic, well-differentiated, neuroendocrine tumors and CS with ≥ four bowel movements (BMs) per day. Somatostatin analog use was allowed. INTERVENTIONS TE, a novel oral inhibitor of peripheral serotonin synthesis. MAIN OUTCOME MEASURES Primary: safety. Secondary: daily BMs, stool form, and u5-HIAA. RESULTS Fifteen patients were enrolled, and 14 completed the treatment period. All patients experienced reductions in BMs per day (mean decrease, 43.5%). A 74.2% mean reduction in u5-HIAA, the main metabolite of serotonin, was observed, with generally greater reductions in patients with greater reductions in BMs per day. Nine patients (75%) reported "adequate relief" of gastrointestinal symptoms at 12 weeks, compared with two (17%) at baseline. Stool form and flushing also improved. Adverse events were mostly gastrointestinal (n = 10; 67%), consistent with underlying illness; three adverse events were serious (abdominal pain, diarrhea, and gastroenteritis) but were judged unrelated. CONCLUSION TE was generally safe and well tolerated. Patients experienced substantial improvement in CS and reductions in u5-HIAA, consistent with the mechanism of action of TE. These results support further evaluation in phase 3 studies.
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