title: Telotristat etiprate for carcinoid syndrome: a single-arm, multicenter trial.
abstract: BACKGROUND
  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).
  
  
  METHODS
  A prospective, exploratory, dose-escalating 12-week, open-label, multicenter study of TE with efficacy and safety analyses.
  
  
  METHODS
  A multicenter study.
  
  
  METHODS
  Eligible patients had metastatic, well-differentiated, neuroendocrine tumors and CS with ≥ four bowel movements (BMs) per day. Somatostatin analog use was allowed.
  
  
  METHODS
  TE, a novel oral inhibitor of peripheral serotonin synthesis.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  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.
authors: Charité - Universitätsmedizin (M.P., B.W.), Department of Gastroenterology and Hepatology, 13353 Berlin Germany; Zentralklinik Bad Berka GmbH (D.H.), Department of Gastroenterology and Endocrinology, 99437 Bad Berka, Germany; Royal Free London National Health Service (NHS) Foundation Trust (M.C.), Department of Gastroenterology and Hepatobiliary Medicine, London NW3 2QG, United Kingdom; Basingstoke and North Hampshire NHS Foundation Trust (J.R.), Department of Gastroenterology, Hampshire RG24 9NA, United Kingdom; Ulm University (T.S.), Department of Internal Medicine I, 89070 Ulm, Germany; The University of Manchester/The Christie NHS Foundation Trust (J.V.), Department of Medical Oncology, Manchester M20 4BX, United Kingdom; and Lexicon Pharmaceuticals, Inc (P.B., P.L., A.S., B.Z., D.F.), Department of Clinical Development, The Woodlands, Texas 77381.
authors: Marianne
authors: M
authors: Pavel
authors: Dieter
authors: D
authors: Hörsch
authors: Martyn
authors: M
authors: Caplin
authors: John
authors: J
authors: Ramage
authors: Thomas
authors: T
authors: Seufferlein
authors: Juan
authors: J
authors: Valle
authors: Phillip
authors: P
authors: Banks
authors: Pablo
authors: P
authors: Lapuerta
authors: Arthur
authors: A
authors: Sands
authors: Brian
authors: B
authors: Zambrowicz
authors: Douglas
authors: D
authors: Fleming
authors: Bertram
authors: B
authors: Wiedenmann
mesh_terms: D015746:Abdominal Pain / Q000188:drug therapy / Q000453:epidemiology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D005483:Flushing / Q000188:drug therapy; D005772:Gastrointestinal Transit / Q000187:drug effects; D006801:Humans; D006897:Hydroxyindoleacetic Acid / Q000652:urine; D008297:Male; D008303:Malignant Carcinoid Syndrome / Q000188:drug therapy* / Q000652:urine; D008875:Middle Aged; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D011743:Pyrimidines / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D011743:Pyrimidines; C000592493:telotristat; D010649:Phenylalanine; D006897:Hydroxyindoleacetic Acid