title: Telotristat etiprate, a novel serotonin synthesis inhibitor, in patients with carcinoid syndrome and diarrhea not adequately controlled by octreotide.
abstract: Serotonin produced by neuroendocrine tumors is believed to be a principal cause of the diarrhea in carcinoid syndrome. We assessed the safety and efficacy of telotristat etiprate, an oral serotonin synthesis inhibitor, in patients with diarrhea associated with carcinoid syndrome. In this prospective, randomized study, patients with evidence of carcinoid tumor and ≥4 bowel movements (BMs)/day despite stable-dose octreotide LAR depot therapy were enrolled in sequential, escalating, cohorts of four patients per cohort. In each cohort, one patient was randomly assigned to placebo and three patients to telotristat etiprate, at 150, 250, 350, or 500 mg three times a day (tid). In a subsequent cohort, one patient was assigned to placebo and six patients to telotristat etiprate 500 mg tid. Patients were assessed for safety, BM frequency (daily diary), 24 h urinary 5-hydroxyindoleacetic acid (u5-HIAA), and adequate relief of carcinoid gastrointestinal symptoms (using a weekly questionnaire). Twenty-three patients were treated: 18 received telotristat etiprate and five received placebo. Adverse events were generally mild. Among evaluable telotristat etiprate-treated patients, 5/18 (28%) experienced a ≥30% reduction in BM frequency for ≥2 weeks, 9/16 (56%) experienced biochemical response (≥50% reduction or normalization in 24-h u5-HIAA) at week 2 or 4, and 10/18 (56%) reported adequate relief during at least 1 of the first 4 weeks of treatment. Similar activity was not observed in placebo-treated patients. Telotristat etiprate was well tolerated. Our observations suggest that telotristat etiprate has activity in controlling diarrhea associated with carcinoid syndrome. Further studies confirming these findings are warranted.
authors.affiliation: Department of Medical OncologyDana-Farber Cancer Institute, 450 Brookline Avenue, Boston, Massachusetts 02115, USAUniversity of Iowa Hospitals and ClinicsIowa City, Iowa, USAThe University of Texas M.D. Anderson Cancer CenterHouston, Texas, USAUCSF Helen Diller Family Comprehensive Cancer CenterSan Francisco, California, USALexicon Pharmaceuticals Inc.The Woodlands, Texas, USAH. Lee Moffitt Cancer CenterTampa, Florida, USA Matthew_Kulke@dfci.harvard.edu.
authors.forename: Matthew H
authors.initials: MH
authors.lastname: Kulke
authors.affiliation: Department of Medical OncologyDana-Farber Cancer Institute, 450 Brookline Avenue, Boston, Massachusetts 02115, USAUniversity of Iowa Hospitals and ClinicsIowa City, Iowa, USAThe University of Texas M.D. Anderson Cancer CenterHouston, Texas, USAUCSF Helen Diller Family Comprehensive Cancer CenterSan Francisco, California, USALexicon Pharmaceuticals Inc.The Woodlands, Texas, USAH. Lee Moffitt Cancer CenterTampa, Florida, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: O'Dorisio
authors.affiliation: Department of Medical OncologyDana-Farber Cancer Institute, 450 Brookline Avenue, Boston, Massachusetts 02115, USAUniversity of Iowa Hospitals and ClinicsIowa City, Iowa, USAThe University of Texas M.D. Anderson Cancer CenterHouston, Texas, USAUCSF Helen Diller Family Comprehensive Cancer CenterSan Francisco, California, USALexicon Pharmaceuticals Inc.The Woodlands, Texas, USAH. Lee Moffitt Cancer CenterTampa, Florida, USA.
authors.forename: Alexandria
authors.initials: A
authors.lastname: Phan
authors.affiliation: Department of Medical OncologyDana-Farber Cancer Institute, 450 Brookline Avenue, Boston, Massachusetts 02115, USAUniversity of Iowa Hospitals and ClinicsIowa City, Iowa, USAThe University of Texas M.D. Anderson Cancer CenterHouston, Texas, USAUCSF Helen Diller Family Comprehensive Cancer CenterSan Francisco, California, USALexicon Pharmaceuticals Inc.The Woodlands, Texas, USAH. Lee Moffitt Cancer CenterTampa, Florida, USA.
authors.forename: Emily
authors.initials: E
authors.lastname: Bergsland
authors.affiliation: Department of Medical OncologyDana-Farber Cancer Institute, 450 Brookline Avenue, Boston, Massachusetts 02115, USAUniversity of Iowa Hospitals and ClinicsIowa City, Iowa, USAThe University of Texas M.D. Anderson Cancer CenterHouston, Texas, USAUCSF Helen Diller Family Comprehensive Cancer CenterSan Francisco, California, USALexicon Pharmaceuticals Inc.The Woodlands, Texas, USAH. Lee Moffitt Cancer CenterTampa, Florida, USA.
authors.forename: Linda
authors.initials: L
authors.lastname: Law
authors.affiliation: Department of Medical OncologyDana-Farber Cancer Institute, 450 Brookline Avenue, Boston, Massachusetts 02115, USAUniversity of Iowa Hospitals and ClinicsIowa City, Iowa, USAThe University of Texas M.D. Anderson Cancer CenterHouston, Texas, USAUCSF Helen Diller Family Comprehensive Cancer CenterSan Francisco, California, USALexicon Pharmaceuticals Inc.The Woodlands, Texas, USAH. Lee Moffitt Cancer CenterTampa, Florida, USA.
authors.forename: Phillip
authors.initials: P
authors.lastname: Banks
authors.affiliation: Department of Medical OncologyDana-Farber Cancer Institute, 450 Brookline Avenue, Boston, Massachusetts 02115, USAUniversity of Iowa Hospitals and ClinicsIowa City, Iowa, USAThe University of Texas M.D. Anderson Cancer CenterHouston, Texas, USAUCSF Helen Diller Family Comprehensive Cancer CenterSan Francisco, California, USALexicon Pharmaceuticals Inc.The Woodlands, Texas, USAH. Lee Moffitt Cancer CenterTampa, Florida, USA.
authors.forename: Joel
authors.initials: J
authors.lastname: Freiman
authors.affiliation: Department of Medical OncologyDana-Farber Cancer Institute, 450 Brookline Avenue, Boston, Massachusetts 02115, USAUniversity of Iowa Hospitals and ClinicsIowa City, Iowa, USAThe University of Texas M.D. Anderson Cancer CenterHouston, Texas, USAUCSF Helen Diller Family Comprehensive Cancer CenterSan Francisco, California, USALexicon Pharmaceuticals Inc.The Woodlands, Texas, USAH. Lee Moffitt Cancer CenterTampa, Florida, USA.
authors.forename: Kenny
authors.initials: K
authors.lastname: Frazier
authors.affiliation: Department of Medical OncologyDana-Farber Cancer Institute, 450 Brookline Avenue, Boston, Massachusetts 02115, USAUniversity of Iowa Hospitals and ClinicsIowa City, Iowa, USAThe University of Texas M.D. Anderson Cancer CenterHouston, Texas, USAUCSF Helen Diller Family Comprehensive Cancer CenterSan Francisco, California, USALexicon Pharmaceuticals Inc.The Woodlands, Texas, USAH. Lee Moffitt Cancer CenterTampa, Florida, USA.
authors.forename: Jessica
authors.initials: J
authors.lastname: Jackson
authors.affiliation: Department of Medical OncologyDana-Farber Cancer Institute, 450 Brookline Avenue, Boston, Massachusetts 02115, USAUniversity of Iowa Hospitals and ClinicsIowa City, Iowa, USAThe University of Texas M.D. Anderson Cancer CenterHouston, Texas, USAUCSF Helen Diller Family Comprehensive Cancer CenterSan Francisco, California, USALexicon Pharmaceuticals Inc.The Woodlands, Texas, USAH. Lee Moffitt Cancer CenterTampa, Florida, USA.
authors.forename: James C
authors.initials: JC
authors.lastname: Yao
authors.affiliation: Department of Medical OncologyDana-Farber Cancer Institute, 450 Brookline Avenue, Boston, Massachusetts 02115, USAUniversity of Iowa Hospitals and ClinicsIowa City, Iowa, USAThe University of Texas M.D. Anderson Cancer CenterHouston, Texas, USAUCSF Helen Diller Family Comprehensive Cancer CenterSan Francisco, California, USALexicon Pharmaceuticals Inc.The Woodlands, Texas, USAH. Lee Moffitt Cancer CenterTampa, Florida, USA.
authors.forename: Larry
authors.initials: L
authors.lastname: Kvols
authors.affiliation: Department of Medical OncologyDana-Farber Cancer Institute, 450 Brookline Avenue, Boston, Massachusetts 02115, USAUniversity of Iowa Hospitals and ClinicsIowa City, Iowa, USAThe University of Texas M.D. Anderson Cancer CenterHouston, Texas, USAUCSF Helen Diller Family Comprehensive Cancer CenterSan Francisco, California, USALexicon Pharmaceuticals Inc.The Woodlands, Texas, USAH. Lee Moffitt Cancer CenterTampa, Florida, USA.
authors.forename: Pablo
authors.initials: P
authors.lastname: Lapuerta
authors.affiliation: Department of Medical OncologyDana-Farber Cancer Institute, 450 Brookline Avenue, Boston, Massachusetts 02115, USAUniversity of Iowa Hospitals and ClinicsIowa City, Iowa, USAThe University of Texas M.D. Anderson Cancer CenterHouston, Texas, USAUCSF Helen Diller Family Comprehensive Cancer CenterSan Francisco, California, USALexicon Pharmaceuticals Inc.The Woodlands, Texas, USAH. Lee Moffitt Cancer CenterTampa, Florida, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Zambrowicz
authors.affiliation: Department of Medical OncologyDana-Farber Cancer Institute, 450 Brookline Avenue, Boston, Massachusetts 02115, USAUniversity of Iowa Hospitals and ClinicsIowa City, Iowa, USAThe University of Texas M.D. Anderson Cancer CenterHouston, Texas, USAUCSF Helen Diller Family Comprehensive Cancer CenterSan Francisco, California, USALexicon Pharmaceuticals Inc.The Woodlands, Texas, USAH. Lee Moffitt Cancer CenterTampa, Florida, USA.
authors.forename: Douglas
authors.initials: D
authors.lastname: Fleming
authors.affiliation: Department of Medical OncologyDana-Farber Cancer Institute, 450 Brookline Avenue, Boston, Massachusetts 02115, USAUniversity of Iowa Hospitals and ClinicsIowa City, Iowa, USAThe University of Texas M.D. Anderson Cancer CenterHouston, Texas, USAUCSF Helen Diller Family Comprehensive Cancer CenterSan Francisco, California, USALexicon Pharmaceuticals Inc.The Woodlands, Texas, USAH. Lee Moffitt Cancer CenterTampa, Florida, USA.
authors.forename: Arthur
authors.initials: A
authors.lastname: Sands
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use; D003967:Diarrhea / Q000188:drug therapy* / Q000652:urine; D005260:Female; D005765:Gastrointestinal Agents / Q000627:therapeutic use; D006801:Humans; D006897:Hydroxyindoleacetic Acid / Q000652:urine; D008297:Male; D008303:Malignant Carcinoid Syndrome / Q000188:drug therapy* / Q000652:urine; D008875:Middle Aged; D015282:Octreotide / Q000627:therapeutic use; D010649:Phenylalanine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D011743:Pyrimidines / Q000009:adverse effects / Q000627:therapeutic use*; D012702:Serotonin Antagonists / Q000009:adverse effects / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D018931:Antineoplastic Agents, Hormonal; D005765:Gastrointestinal Agents; D011743:Pyrimidines; D012702:Serotonin Antagonists; C000592493:telotristat; D010649:Phenylalanine; D006897:Hydroxyindoleacetic Acid; D015282:Octreotide
keywords: adult; carcinoid syndrome; diarrhea; neuroendocrine tumor; serotonin; tryptophan hydroxylase