Telotristat ethyl relieves symptoms in carcinoid syndrome

Reuters Health Information: Telotristat ethyl relieves symptoms in carcinoid syndrome

Telotristat ethyl relieves symptoms in carcinoid syndrome

Last Updated: 2016-11-15

By Will Boggs MD

NEW YORK (Reuters Health) - The tryptophan hydroxylase inhibitor telotristat ethyl reduces bowel movement frequency and urinary 5-hydroxyindole acetic acid (u5-HIAA) levels in patients with carcinoid syndrome, according to results of a phase 3 trial.

Patients with advanced neuroendocrine tumors can develop carcinoid syndrome, which is associated with tumoral secretion of serotonin (reflected in high u5-HIAA levels). The condition is characterized by diarrhea, flushing, bronchial constriction, and the development of cardiac valvular fibrosis. Carcinoid syndrome is typically treated with somatostatin analogues (SSAs).

Dr. Matthew H. Kulke from Dana-Farber Cancer Institute in Boston and colleagues assessed the safety and efficacy of telotristat ethyl in a randomized trial of 135 patients not adequately controlled with SSA therapy.

At baseline, average daily bowel movement (BM) frequency ranged from 5.2 to 6.1 per day and mean u5-HIAA levels ranged from 81.0 to 92.6 mg/24 hours, the researchers report in the Journal of Clinical Oncology, online October 28.

Average daily BM frequency declined by 1.7 per day with telotristat ethyl 250 mg and by 2.1 per day with telotristat ethyl 500 mg, significantly more than the decline of 0.9 per day seen in the placebo group.

More than 40% of participants who received telotristat ethyl (44% with 250 mg and 42% with 500 mg) were classified as BM responders (>=30% reduction in BM frequency for >=50 of the treatment period), versus 20% of patients who received placebo.

Mean u5-HIAA levels decreased significantly in both telotristat ethyl groups, but increased in the placebo group, at week 12.

Scores on the quality-of-life diarrhea subscale improved to a greater extent in both telotristat ethyl groups than in the placebo group, although the groups did not differ in global health status.

The overall incidence of treatment-emergent adverse events was similar across the treatment groups. But nausea was more common in the higher-dose telotristat ethyl group, and dose-related increases in gamma-glutamyl transferase were seen in both telotristat ethyl groups.

"These observations suggest that telotristat ethyl represents a potential new treatment approach for patients with carcinoid syndrome," the researchers conclude.

Dr. Daniel Rayson from Dalhousie University in Halifax, Canada, who recently reviewed the evidence-based diagnosis and management of gastrointestinal neuroendocrine tumors, told Reuters Health by email, "Most interesting was the observation that >78% of the patients on the active treatment arms experienced a 24-hr urinary 5-HIAA decrease of >=30%, which, as the authors suggest, may lead to further investigation of this agent in the prevention of mesenteric fibrosis and carcinoid heart disease, two of the most significant complications arising from uncontrolled serotonin secretion."

"Symptomatic carcinoid syndrome results in symptoms that impact patient quality of life over a long period of time due to the generally indolent pace of disease progression for the majority of patients," he said. "Diarrhea is the most disruptive symptom in terms of daily quality of life and may be favorably impacted by this new therapeutic option."

"It is also important to remember that 30-40% of patients have alternative etiologies for diarrhea including bile salt malabsorption, ileocecal valve dysfunction, and/or pancreatic insufficiency, and these all should be considered in patient management," Dr. Rayson said.

Lexicon Pharmaceuticals supported the study. Several authors reported financial ties to the company, including employment.

Dr. Kulke did not respond to a request for comments.

SOURCE: http://bit.ly/2f0Njll

J Clin Oncol 2016.

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