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).
Highlights
IntroductionElevated levels of serotonin occur mainly in metastatic disease and are associated with diarrhea, one of the most common symptoms of Carcinoid syndrome (CS), and the development of carcinoid heart disease; further, high levels of urinary metabolite 5-hydroxyindoleacetic acid (u5-HIAA) in patients with neuroendocrine tumors (NETs) have been associated with poor survival (Moertel 1987, van der Horst-Schrivers et al 2007, Boudreaux et al 2010, National Cancer Institute 2015, National Comprehensive Cancer Network 2017)
Carcinoid syndrome (CS) is a disorder that develops in up to 20% of patients with neuroendocrine tumors (NETs) and is characterized by severe diarrhea, flushing, abdominal pain, and eventually cardiac valvular complications, which can lead to heart failure (Fox & Khattar 2004, Mamikunian et al 2009, National Cancer Institute 2015, Davar et al 2017, Halperin et al 2017, National Comprehensive Cancer Network 2017)
The phase 3 TELESTAR study demonstrated that treatment with telotristat ethyl was generally well tolerated and was associated with significant reductions in bowel movement (BM) frequency and urinary metabolite 5-hydroxyindoleacetic acid (u5-HIAA) levels in patients with CS not adequately controlled by somatostatin analogs (SSAs) therapy (≥4 BMs per day (BMs/day) while receiving SSAs)
Summary
Elevated levels of serotonin occur mainly in metastatic disease and are associated with diarrhea, one of the most common symptoms of CS, and the development of carcinoid heart disease; further, high levels of u5-HIAA in patients with NETs have been associated with poor survival (Moertel 1987, van der Horst-Schrivers et al 2007, Boudreaux et al 2010, National Cancer Institute 2015, National Comprehensive Cancer Network 2017). The phase 3 TELESTAR study demonstrated that treatment with telotristat ethyl was generally well tolerated and was associated with significant reductions in bowel movement (BM) frequency and u5-HIAA levels in patients with CS not adequately controlled by SSA therapy (≥4 BMs per day (BMs/day) while receiving SSAs). Telotristat ethyl at a dosage of 250 mg 3 times per day was recently approved by the US Food and Drug Administration and the European Commission and is a category 2A recommendation in the National Comprehensive Cancer Network clinical practice guidelines for the treatment of CS diarrhea inadequately controlled by SSA therapy (European Commission 2017, FDA News Release 2017, Lexicon Pharmaceuticals 2017, National Comprehensive Cancer Network 2017)
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