Telotristat ethyl in carcinoid syndrome: safety and efficacy in the TELECAST phase 3 trial

Endocrine-Related Cancer - Tập 25 Số 3 - Trang 309-322 - 2018
Marianne Pavel1, David J. Gross2, Marta Benavent3,4, Petros Perros5, Rajaventhan Srirajaskanthan6, Richard R.P. Warner7, Matthew H. Kulke8, Lowell Anthony9, Pamela L. Kunz10, Dieter Hörsch11, Martin O. Weickert12, Pablo Lapuerta13, Wenjun Jiang13, Kenneth Kassler-Taub13, Suman Wason13, Rosanna Fleming13, Douglas Fleming14,15, Rocio García‐Carbonero16,17
1Department of Gastroenterology and Hepatology, Charité-Universitätsmedizin, Berlin, Germany
2Neuroendocrine Tumor Unit, Endocrinology and Metabolism Service, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
3Laboratorio de Oncología Molecular y Nuevas Terapias, Instituto de Biomedicina de Sevilla, Sevilla, Spain
4Medical Oncology Department, Hospital Universitario Virgen del Rocio, Sevilla, Spain
5Department of Endocrinology, Royal Victoria Infirmary, Newcastle upon Tyne, UK
6Neuroendocrine Tumour Unit, Institute of Liver Studies, Kings College Hospital, London, UK
7Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, New York, USA
8Medical Oncology/Solid Tumor Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
9Division of Medical Oncology, University of Kentucky, Lexington, Kentucky, USA
10Department of Medicine, Stanford University School of Medicine, Palo Alto, California USA.
11Department of Gastroenterology/Endocrinology, Zentralklinik Bad Berka, Bad Berka, Germany
12The ARDEN NET Centre, ENETS Centre of Excellence, University Hospitals Coventry and Warwickshire NHS Trust, Coventry, UK
13Lexicon Pharmaceuticals, Inc., The Woodlands, Texas, USA
14(D Fleming is now at Bristol-Myers Squibb, Princeton, New Jersey, USA
15Ipsen Bioscience, Cambridge, Massachusetts, USA
16CIBERONC, Madrid, Spain
17Oncology Department, Hospital Universitario 12 de Octubre, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), UCM, CNIO,

Tóm tắt

Telotristat ethyl, a tryptophan hydroxylase inhibitor, was efficacious and well tolerated in the phase 3 TELESTAR study in patients with carcinoid syndrome (CS) experiencing ≥4 bowel movements per day (BMs/day) while on somatostatin analogs (SSAs). TELECAST, a phase 3 companion study, assessed the safety and efficacy of telotristat ethyl in patients with CS (diarrhea, flushing, abdominal pain, nausea or elevated urinary 5-hydroxyindoleacetic acid (u5-HIAA)) with <4 BMs/day on SSAs (or ≥1 symptom or ≥4 BMs/day if not on SSAs) during a 12-week double-blind treatment period followed by a 36-week open-label extension (OLE). The primary safety and efficacy endpoints were incidence of treatment-emergent adverse events (TEAEs) and percent change from baseline in 24-h u5-HIAA at week 12. Patients (N = 76) were randomly assigned (1:1:1) to receive placebo or telotristat ethyl 250 mg or 500 mg 3 times per day (tid); 67 continued receiving telotristat ethyl 500 mg tid during the OLE. Through week 12, TEAEs were generally mild to moderate in severity; 5 (placebo), 1 (telotristat ethyl 250 mg) and 3 (telotristat ethyl 500 mg) patients experienced serious events, and the rate of TEAEs in the OLE was comparable. At week 12, significant reductions in u5-HIAA from baseline were observed, with Hodges–Lehmann estimators of median treatment differences from placebo of −54.0% (95% confidence limits, −85.0%, −25.1%,P < 0.001) and −89.7% (95% confidence limits, −113.1%, −63.9%,P < 0.001) for telotristat ethyl 250 mg and 500 mg. These results support the safety and efficacy of telotristat ethyl when added to SSAs in patients with CS diarrhea (ClinicalTrials.gov identifier: Nbib2063659).

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Endocrine-Related Cancer

Tập 25 Số 3

309-322

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