Telotristat etiprate, a novel serotonin synthesis inhibitor, in patients with carcinoid syndrome and diarrhea not adequately controlled by octreotide

Abstract

Serotonin produced by neuroendocrine tumors is believed to be a principal cause of the diarrhea in carcinoid syndrome. We assessed the safety and efficacy of telotristat etiprate, an oral serotonin synthesis inhibitor, in patients with diarrhea associated with carcinoid syndrome. In this prospective, randomized study, patients with evidence of carcinoid tumor and ≥4 bowel movements (BMs)/day despite stable-dose octreotide LAR depot therapy were enrolled in sequential, escalating, cohorts of 4 patients/cohort. In each cohort, 1 patient was randomly assigned to placebo and 3 patients to telotristat etiprate, at 150, 250, 350, or 500 mg 3x/day (tid). In a subsequent cohort, 1 patient was assigned to placebo and 6 patients to telotristat etiprate 500 mg tid. Patients were assessed for safety, BM frequency (daily diary), 24-hour urinary 5-hydroxyindoleacetic acid (u5-HIAA), and adequate relief of carcinoid gastrointestinal symptoms (using a weekly questionnaire). Twenty-three patients were treated; 18 received telotristat etiprate and 5 received placebo. Adverse events were generally mild. Among evaluable telotristat etiprate-treated patients, 5/18 (28%) experienced a ≥30% reduction in BM frequency for ≥2 weeks, 9/16 (56%) experienced biochemical response (≥50% reduction or normalization in 24-hour u5-HIAA) at Week 2 or 4, and 10/18 (56%) reported adequate relief during at least 1 of the first 4 weeks of treatment. Similar activity was not observed in placebo-treated patients. Telotristat etiprate was well tolerated. Our observations suggest that telotristat etiprate has activity in controlling diarrhea associated with carcinoid syndrome. Further studies confirming these findings are warranted.

Do we really care about incidental lung nodules?—Review of atypical lung carcinoid and a proposal for systematic patient follow up

“…Hormonally active grade 1 and 2 tumors are usually started on SSA treatment (2,5). SSA resistant tumors may benefit from additional serotonin synthesis inhibitor, telotristat etiprate (10). Grade 3 tumors are initially treated with chemotherapy (3).…”

Summary of emerging personalized medicine in neuroendocrine tumors: are we on track?

“…Instead, diazoxide, which suppresses insulin release from pancreatic beta cells, is commonly used to control hypoglycemia in unresectable symptomatic insulinoma (18), and the use of SSAs is often reserved for cases refractory to diazoxide. Telotristat etiprate, an oral inhibitor of serotonin synthesis, significantly improved symptoms of refractory carcinoid syndrome and decreased urinary 5-HIAA levels in early phase clinical trials (19,20), and the randomized, double-blind, placebo-controlled phase III TELESTAR trial in patients with refractory carcinoid syndrome demonstrated that adding telotristat etiprate to SSA significantly improved symptoms of carcinoid syndrome (21).…”

WOMEN IN CANCER PROFILE: Neuroendocrine tumors: moving from the land of small tumors to an expanding universe

“…It is a great advancement to have the first drug approved for lung NET and to have options beyond SSA in GI NET. Further, next to Matthew Kulke's group at Dana Faber University, Boston, we first explored LX1606, an oral tryptophan hydroxylase inhibitor, in patients with refractory carcinoid syndrome (NCT00853047, NCT01104415), while on therapy with somatostatin analogs (Kulke et al 2014, Pavel et al 2015. These small phase II studies in patients with carcinoid syndrome fulfilled an unmet need in patients suffering from diarrhea related to serotonin hypersecretion.…”