The investigational drug telotristat etiprate was shown to have clinical benefit when added to somatostatin analog therapy for carcinoid syndrome not adequately controlled by long-acting somatostatin analog therapy, the current standard of care, in patients with metastatic neuroendocrine tumors. Matthew H. Kulke, MD, primary investigator of the phase III TELESTAR study, presented these findings at the European Cancer Congress held recently in Vienna.1
Dr. Kulke is Director, Program in Neuroendocrine and Carcinoid Tumors and Senior Physician, Dana-Farber Cancer Institute, and Associate Professor of Medicine, Harvard Medical School.
Carcinoid syndrome, characterized by debilitating diarrhea, facial flushing, abdominal pain, heart valve damage, and other serious consequences, is triggered by excess serotonin production within the cells of metastatic neuroendocrine tumors. Telotristat etiprate targets tryptophan hydroxylase, an enzyme that triggers this excess serotonin production, leading to carcinoid syndrome in patients with neuroendocrine tumors.
TELESTAR Study
The double-blind phase III TELESTAR study enrolled 135 patients with metastatic neuroendocrine tumors and who had carcinoid syndrome that was not adequately controlled on somatostatin analog therapy. The three-arm study evaluated two doses of oral telotristat etiprate—250 mg and 500 mg—each taken three times per day vs placebo over a 12-week period.
Investigators measured the reduction from baseline in the average number of daily bowel movements. Patients in both of the telotristat etiprate arms and in the placebo arm continued their somatostatin analog therapy throughout the study.
Data showed that patients who received telotristat etiprate added to somatostatin analog therapy at both the 250-mg and 500-mg doses experienced a statistically significant reduction from baseline compared to placebo in the average number of daily bowel movements over the 12-week study period (P < .001), thus meeting the study’s primary endpoint.
Patients who received 250 mg of telotristat etiprate experienced a reduction of 1.71 bowel movements (29%) in the average number of daily bowel movements during the final week of the study compared to baseline, and those in the 500-mg arm experienced a reduction of 2.11 bowel movements (35%); the placebo group showed a reduction of 0.87 bowel movements (17%).
Durable Responses
A substantially greater proportion of patients on telotristat etiprate/somatostatin analog therapy achieved a durable response (44% and 42% in the 250-mg and 500-mg arms, respectively), defined as at least a 30% reduction in daily bowel movements over at least half the days of the study period, as compared to 20% response in patients receiving the placebo plus somatostatin analog therapy (P < .02).
The mean change in urinary 5-HIAA, the main metabolite of serotonin, from baseline to week 12 was a reduction of 40 mg/24 hours in the 250-mg arm and 58 mg/24 hours in the 500-mg arm. These changes compared with an increase in urinary 5-HIAA of 11 mg/24 hours in the placebo group (P < .001). Baseline urinary 5-HIAA levels were 93 mg/24 hours in the 250-mg arm, 90 mg/24 hours in the 500-mg arm, and 81 mg/24 hours in the placebo group.
Tolerability
Treatment with telotristat etiprate was generally well tolerated during the double-blind treatment period. The proportions of patients with treatment-emergent adverse events were 82% in the 250-mg arm, 93% in the 500-mg arm, and 87% in the placebo group during the 12-week study period. The proportions of patients who discontinued treatment due to adverse events in both the 250-mg and 500-mg arms were 7% as compared to 13% in the placebo group.
Patients who received telotristat etiprate added to somatostatin analog therapy also experienced a lower frequency of flushing episodes and less intense abdominal pain compared to those receiving the placebo with somatostatin analog therapy. These differences did not reach statistical significance.
Efficacy and Safety Data
“Telotristat etiprate represents a novel approach by specifically inhibiting serotonin synthesis and, as such, is a promising potential new treatment for patients whose lives can be significantly impacted by this debilitating condition,” said Dr. Kulke. “These results are exciting from both an efficacy and safety perspective for [patients with] carcinoid syndrome.”
The tolerability profile of the telotristat etiprate 250-mg dose appeared similar to placebo and somewhat better than the 500-mg dose in terms of gastrointestinal discomfort and mood. There were 6 events of patients experiencing mild to moderate nausea in the 250-mg arm, 13 in the 500-mg arm, and 5 in the placebo group. There were 2 events of depression or depressed mood in the 250-mg arm, 8 in the 500-mg arm, and 3 in the placebo group. There were no discontinuations of treatment due to nausea, depression, or depressed mood in the 250-mg and 500-mg arms during the 12-week study period.
“Carcinoid syndrome has a significant impact on the lives of patients who already have been battling metastatic cancer,” said Maryann Wahmann, Founder and President of the Neuroendocrine Cancer Awareness Network. “These patients can live for many years with their cancer, yet the symptoms of carcinoid syndrome are what frequently limit their lives and restrict their activities every single day. So there is a tremendous need for effective new treatment options.”
Telotristat etiprate has received Fast Track and Orphan Drug designation from the U.S. Food and Drug Administration. ■
Disclosure: Dr. Kulke reported no potential conflicts of interest.
Reference
1. Kulke M, Hörsch D, Caplin M, et al: Telotristat etiprate is effective in treating patients with carcinoid syndrome that is inadequately controlled by somatostatin analog therapy: The phase III TELESTAR clinical trial. 2015 European Cancer Congress. Abstract 37LBA. Presented September 29, 2015.
