Table 3.
Phase III clinical trial designs with telotristat ethyl
| TELESTAR (Kulke, 2016)77 | TELECAST (Pavel, 2018)78 | |
|---|---|---|
| Number of patients | 135 | 76 |
| Study design | Prospective, randomized (1:1:1 ratio), placebo-controlled | Prospective, randomized (1:1:1 ratio), placebo-controlled |
| Treatment arms | Telotristat ethyl 250 mg versus Telotristat ethyl 500 mg versus placebo | Telotristat ethyl 250 mg versus telotristat ethyl 500 mg versus placebo |
| Inclusion criteria | ≥18 years old WD-NET biopsy-proven Refractory carcinoid syndrome Stable-dose of SSA for at least 3 months before inclusion |
≥18 years old WD-NET biopsy-proven Documented carcinoid syndrome Stable-dose of SSA for at least 3 months before inclusion |
| Refractory carcinoid syndrome | ≥4BM per day despite SSA treatment for at least 3 months before inclusion u5-HIAA could be above or below the ULN, or unknown |
<4BM per day with a stable dose of SSA, and at least one of the following: - Daily stool consistency ≥5 on the Bristol stool form scale for ≥50% of the days - Daily flushing frequency of ≥2 - Daily rating of ≥3 episodes of abdominal pain - Nausea present ≥20% of the days - u5-HIAA above the ULN Or ≥4BM per day or at least one of the previous items if patient was not on SSA therapy |
| Response | Reduction of at least 30% in BM per day from the baseline | Reduction of at least 30% in BM per day from the baseline Durable: at least 50% of the time in 12 weeks |
| Primary aim | Mean reduction from baseline in daily BM averaged over 12 weeks | Safety: incidence of treatment-emergent adverse events Efficacy: percent change from baseline in 24 hr u5-HIAA levels at week 12 |
| Safety | No serious AE reported. Most of the AE were gastrointestinal (nausea, abdominal pain, vomiting) Depression-related AE occurred in 6.7% of both telotristat ethyl arms and 15.6% of placebo arms. No patient required antidepressant drugs |
No depression-related AE on telotristat ethyl. Two depression-related AE in the expansion phase (OLE) in patients with previous diagnosis of depression at baseline. Gastrointestinal AE mainly, milda: abdominal pain, nausea, vomiting, constipation. Not dose-dependent |
| Efficacy | Mean reduction in daily BM frequency from baseline to week 12 was −1.7 and −2.1 with telotristat ethyl 250 mg and 500 mg, respectively, and −0.9 for the placebo arm 42–44% of patients in telotristat ethyl groups are considered as responders. u5-HIAA levels decreased significantly with telotristat ethyl, but increased in placebo arm Slight improvements in other parameters (abdominal pain, urgency, stools consistency, flushing): not statistically significant |
A significant reduction from baseline in u5-HIAA levels at week 12 for both telotristat ethyl arms compared with placebo (−76.5 and −33.2% with telotristat ethyl 500 mg and 250 mg, respectively) 40% considered durable responders in telotristat ethyl groups telotristat ethyl 500 mg had a statistically significant effect on stool consistency. This difference was not achieved between the telotristat ethyl 250 mg and placebo No statistically significant changes in flushing or abdominal pain |
Note: aMild: adverse events were graded in severity by the investigator as mild, moderate or severe.
Abbreviations: WD-NET, well-differentiated neuroendocrine tumor; SSA, somatostatin analogs; BM, bowel movements; u5-HIAA, urinary 5-hydroxyindoleacetic acid; ULN, upper limit of normal; AE, adverse events.