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).

Systemic Treatment Options for Carcinoid Syndrome: A Systematic Review

“…All 12 studies reported efficacy and safety data from prospective, interventional, phase II or III clinical trials or pivotal clinical trials leading to drug approval; 3 were phase II [15-17], 6 were phase III [11-14, 18, 22], 1 was phase II/III [19], and 2 did not meet criteria for a phase II or III trial but were considered to be pivotal trials [20, 21]. The studies examined included 1,366 participants with NET, of which at least 1,137 had carcinoid syndrome.…”

“…In the double-blind randomized phase III trial TELESTAR, telotristat ethyl significantly reduced bowel movement frequency with either the 250 or 500 mg TID dose versus placebo in patients with symptomatic carcinoid diarrhea while receiving stable-dose long-acting SSAs [12], and this antidiarrheal effect was confirmed by the double-blind randomized phase III TELECAST companion study of patients with carcinoid syndrome diarrhea (with or without SSA treatment) [11]. In TELESTAR and TELECAST, 40–44% of patients met predefined symptom response criteria in terms of bowel movement frequency reduction, compared with 0–20% of placebo-treated patients [11, 12].…”

“…In TELESTAR and TELECAST, 40–44% of patients met predefined symptom response criteria in terms of bowel movement frequency reduction, compared with 0–20% of placebo-treated patients [11, 12]. Both trials reported a significant decrease in u5-HIAA but no change in flushing frequency or daily use of a rescue short-acting SSA [11, 12]. …”

“…GI events such as nausea and abdominal pain were commonly reported among the studies of long-acting SSAs, telotristat ethyl, and 177 Lu-Dotatate PRRT, including the ELECT trial of lanreotide autogel/depot, the placebo + long-acting octreotide arm of the RADIANT-2 trial, the TELESTAR and TELECAST trials of telotristat ethyl, and the NETTER-1 trial of 177 Lu-Dotatate and high-dose long-acting octreotide [11-13, 17, 18, 22]. In the ELECT study, diarrhea and flushing events were not captured as adverse events, owing to the overlap with disease symptoms that were captured in separate study end points [13]; however, all other studies included diarrhea and flushing in adverse event frequencies.…”

“…In the ELECT study, diarrhea and flushing events were not captured as adverse events, owing to the overlap with disease symptoms that were captured in separate study end points [13]; however, all other studies included diarrhea and flushing in adverse event frequencies. Importantly, the TELECAST trial established that the GI events observed were not related to treatment with telotristat ethyl, except for one case of constipation [11]. Nausea and vomiting observed with 177 Lu-Dotatate treatment were found to be attributed to amino acid infusions performed concurrently with PRRT in the majority of cases, and these events resolved once the infusions were completed [22].…”