Among patients with carcinoid syndrome not adequately controlled by stable-dose somatostatin analogs, treatment with telotristat ethyl was generally safe and well tolerated and resulted in significant reductions in [bowel movement] frequency and [urinary] 5-HIAA.

— Matthew H. Kulke, MD

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In the phase III TELESTAR trial reported in the Journal of Clinical ­Oncology by Matthew H. Kulke, MD, of Dana-Farber Cancer Institute, and colleagues, telotristat ethyl, an investigational tryptophan hydroxylase inhibitor, significantly reduced the frequency of bowel movements in patients with metastatic neuroendocrine tumors and carcinoid syndrome.¹ Telotristat ethyl treatment was also associated with significantly reduced levels of urinary 5-hydroxyindoleacetic acid (5-HIAA), a marker for systemic serotonin levels, which are typically elevated in severe carcinoid syndrome.

Study Details

In the trial, 135 patients from sites in 12 countries were randomized 1:1:1 between January 2013 and March 2015 to receive oral telotristat ethyl at 250 mg (n = 45) or 500 mg (n = 45) or placebo (n = 45) 3 times daily during a 12-week double-blind treatment period. Patients had well-differentiated metastatic neuroendocrine tumors and a documented history of carcinoid syndrome, were experiencing an average of at least 4 bowel movements per day, and were receiving stable-dose somatostatin analog treatment for at least 3 months prior to enrollment. Patients remained on baseline stable-dose somatostatin analog therapy for the 12-week period. The primary endpoint was change from baseline in the frequency of bowel movements.

Overall, 44% of patients were receiving above-label doses of stable-dose somatostatin analogs, and approximately 57% had urinary 5-HIAA levels above the upper limit of normal. Across treatment groups, the mean daily frequency of bowel movements ranged from 5.2 to 6.1 per day, and mean urinary 5-HIAA levels ranged from 81.0 to 92.6 mg/24 h.

Frequency of Bowel Movements

At week 12, reductions in the mean frequency of bowel movements per day were –0.9 with placebo, –1.7 with telotristat ethyl at 250 mg, and –2.1 with telotristat ethyl at 500 mg. Compared with placebo, the estimated difference in bowel movement frequency averaged over 12 weeks was –0.81 per day with telotristat ethyl at 250 mg (P < .001) and –0.69 per day with telotristat ethyl at 500 mg (P < .001).

Response—defined as a reduction in the frequency of bowel movements ≥ 30% from baseline for ≥ 50% of the 12-week period—was observed in 20% of the placebo group, 44% of the 250-mg telotristat ethyl group (odds ratio = 3.49, 95% confidence interval [CI] = 1.33–9.16), and 42% of the 500-mg telotristat ethyl group (odds ratio = 3.11, 95% CI = 1.20–8.10).

Mean urinary 5-HIAA levels decreased by 40.1 mg/24 h (P < .001) and 57.7 mg/24 hours (P < .001) in the 250-mg and 500-mg telotristat ethyl groups vs a mean increase of 11.5 mg/24 h in the placebo group. In a post hoc analysis, a ≥ 30% reduction occurred in 78% and 87% vs 10% of patients, respectively.

Adverse Events

Nausea occurred in 31.1% of the 500-mg telotristat ethyl group, 13.3% of the 250-mg group, and 11.1% of the placebo group. Abdominal pain occurred in 22.2%, 11.1%, and 17.8%, respectively. Gamma-glutamyl transferase levels were elevated in 8.9%, 8.9%, and 0%, and alanine transaminase levels increased in 6.7%, 2.2%, and 0%. Depression-related adverse events occurred in 15.6%, 6.7%, and 6.7%. Treatment was discontinued due to adverse events in 6.7%, 6.7%, and 13.3%.

Over the treatment period, average diarrhea subscale scores on the European Organisation for Research and Treatment of Cancer (EORTC) Quality-of-Life Questionnaire–Core 30 (QLQ-C30) improved by 19.2 points (P = .039) and 21.6 points (P = .051) on a 0-to-100 scale in the 250-mg and 500-mg telotristat ethyl groups vs 8.5 points in the placebo group. No significant differences among groups were observed in the nausea and vomiting subscale or in the global health status subscale. Some evidence of improved overall quality of life in responders vs nonresponders was reported in all groups.

In an open-label extension, 115 patients received telotristat ethyl at 500 mg. Mean treatment exposure was 26.7 weeks. Reduction in the frequency of bowel movements was consistent with that in the double-blind treatment period, and no new safety signals were observed.

The investigators concluded: “Among patients with carcinoid syndrome not adequately controlled by stable-dose somatostatin analogs, treatment with telotristat ethyl was generally safe and well tolerated and resulted in significant reductions in [bowel movement] frequency and [urinary] 5-HIAA.” ■

Disclosure: The study was funded by Lexicon Pharmaceuticals Inc. For full disclosures of the study authors, visit jco.ascopubs.org.

Reference

1. Kulke MH, Hörsch D, Caplin ME, et al: Telotristat ethyl, a tryptophan hydroxylase inhibitor for the treatment of carcinoid syndrome. J Clin Oncol 35:14-23, 2017.