Telotristat Ethyl, a Tryptophan Hydroxylase Inhibitor for the Treatment of Carcinoid Syndrome.

Abstract

Purpose Preliminary studies suggested that telotristat ethyl, a tryptophan hydroxylase inhibitor, reduces bowel movement (BM) frequency in patients with carcinoid syndrome. This placebo-controlled phase III study evaluated telotristat ethyl in this setting. Patients and Methods Patients (N = 135) experiencing four or more BMs per day despite stable-dose somatostatin analog therapy received (1:1:1) placebo, telotristat ethyl 250 mg, or telotristat ethyl 500 mg three times per day orally during a 12-week double-blind treatment period. The primary end point was change from baseline in BM frequency. In an open-label extension, 115 patients subsequently received telotristat ethyl 500 mg. Results Estimated differences in BM frequency per day versus placebo averaged over 12 weeks were -0.81 for telotristat ethyl 250 mg ( P < .001) and ‒0.69 for telotristat ethyl 500 mg ( P < .001). At week 12, mean BM frequency reductions per day for placebo, telotristat ethyl 250 mg, and telotristat ethyl 500 mg were -0.9, -1.7, and -2.1, respectively. Responses, predefined as a BM frequency reduction ≥ 30% from baseline for ≥ 50% of the double-blind treatment period, were observed in 20%, 44%, and 42% of patients given placebo, telotristat ethyl 250 mg, and telotristat ethyl 500 mg, respectively. Both telotristat ethyl dosages significantly reduced mean urinary 5-hydroxyindole acetic acid versus placebo at week 12 ( P < .001). Mild nausea and asymptomatic increases in gamma-glutamyl transferase were observed in some patients receiving telotristat ethyl. Follow-up of patients during the open-label extension revealed no new safety signals and suggested sustained BM responses to treatment. Conclusion Among patients with carcinoid syndrome not adequately controlled by somatostatin analogs, treatment with telotristat ethyl was generally safe and well tolerated and resulted in significant reductions in BM frequency and urinary 5-hydroxyindole acetic acid.

• Authors: Matthew H Kulke, Dieter Hörsch, Martyn E Caplin, Lowell B Anthony, Emily Bergsland, Kjell Öberg, Staffan Welin, Richard R P Warner, Catherine Lombard-Bohas, Pamela L Kunz, Enrique Grande, Juan W Valle, Douglas Fleming, Pablo Lapuerta, Phillip Banks, Shanna Jackson, Brian Zambrowicz, Arthur T Sands, Marianne Pavel
• Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology (J Clin Oncol) Vol. 35 Issue 1 Pg. 14-23 (Jan 2017) ISSN: 1527-7755 [Electronic] United States
• PMID: 27918724 (Publication Type: Clinical Trial, Phase III, Journal Article, Multicenter Study, Randomized Controlled Trial)

Chemical References

• Antineoplastic Agents, Hormonal
• Gastrointestinal Agents
• Peptides, Cyclic
• Pyrimidines
• lanreotide
• Phenylalanine
• Somatostatin
• Hydroxyindoleacetic Acid
• telotristat ethyl
• Tryptophan Hydroxylase
• gamma-Glutamyltransferase
• Octreotide

Topics

• Aged
• Antineoplastic Agents, Hormonal (therapeutic use)
• Defecation (drug effects)
• Diarrhea (drug therapy, etiology, urine)
• Double-Blind Method
• Female
• Gastrointestinal Agents (therapeutic use)
• Humans
• Hydroxyindoleacetic Acid (urine)
• Male
• Malignant Carcinoid Syndrome (complications, drug therapy, urine)
• Middle Aged
• Nausea (chemically induced)
• Octreotide (therapeutic use)
• Peptides, Cyclic (therapeutic use)
• Phenylalanine (adverse effects, analogs & derivatives, therapeutic use)
• Pyrimidines (adverse effects, therapeutic use)
• Somatostatin (analogs & derivatives, therapeutic use)
• Tryptophan Hydroxylase (antagonists & inhibitors)
• gamma-Glutamyltransferase (blood)