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

Abstract

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).

Trial registration: ClinicalTrials.gov NCT02063659.

Keywords: 5-HIAA; carcinoid syndrome; metastatic neuroendocrine tumor; serotonin; somatostatin analog.

Figure 1

CONSORT diagram of the TELECAST clinical trial. Patient flow in the TELECAST study. DBT, double-blind treatment; OLE, open-label extension; tid, 3 times per day.

Figure 2

Changes in u5-HIAA levels from baseline. (A) The Hodges–Lehmann (HL) estimator, a nonparametric measure used to describe the magnitude of treatment effect, was assessed at week 12 (^aP < 0.001). ^bData include 1 patient who experienced a 1864.5% increase from baseline. ^cThe colors and shapes in each bar represent the assigned treatment group during the double-blind treatment (DBT) period; clear bars with filled shapes indicate treatment of these patients with telotristat ethyl 500 mg 3 times per day (tid) during the open-label extension (OLE) period. (B) The distribution of individual patient responses to treatment with telotristat ethyl 250 mg tid or placebo, as percent change from baseline at week 12. One patient treated with placebo had a 1864.5% change from baseline and is not included in the figure. (C) The distribution of individual patient responses to treatment with telotristat ethyl 500 mg tid or placebo, as percent change from baseline at week 12. One patient treated with placebo had a 1864.5% change from baseline and is not included in the figure. u5-HIAA, urinary 5-hydroxyindoleacetic acid.

Figure 3

Mean changes from baseline (B) in frequency of bowel movements per day. The change in mean daily bowel movement (BM) frequency was assessed weekly over the double-blind treatment (DBT) and open-label extension (OLE) periods of the study. The dotted lines indicate the crossover of patients from either placebo or telotristat ethyl 250 mg 3 times per day (tid) to telotristat ethyl 500 mg tid in the OLE period.