37LBA Telotristat etiprate is effective in treating patients with carcinoid syndrome that is inadequately controlled by somatostatin analog therapy (the phase 3 TELESTAR clinical trial)

Abstract

Background: Overproduction of serotonin from within metastatic neuroen- docrine tumors (NET) causes carcinoid syndrome (CS), which includes frequent bowel movements (BMs), diarrhea, flushing, abdominal pain and heart valve damage. Telotristat etiprate (TE) inhibits tryptophan hydroxylase (TPH), the rate-limiting enzyme for conversion of tryptophan to serotonin in the NET cell. TELESTAR is a pivotal phase 3 global clinical trial. Materials and Methods: 135 patients with metastatic NETs and inadequately controlled CS ( 4 daily BMs despite stable dose SSA therapy) were randomly assigned (1:1:1) to receive TE (250 or 500 mg) or placebo (PBO) given tid, while continuing SSA. The primary objective was to confirm that TE was effective in reducing the mean number of daily BMs averaged over the 12-week double-blind period of the trial. Secondary objectives included changes in urinary 5-hydroxyindoleacetic acid (u5-HIAA, a serotonin metabolite), cutaneous flushing episodes, and abdominal pain. Results: Of the 135 patients enrolled, 45 were assigned to each treatment group. Demographics were similar across the 3 treatment groups; mean age 64 years, baseline mean number of BMs/day 5.7. The primary objective was met, as both TE groups reduced mean BM frequency greater than PBO (p < 0.001; Hodges Lehman Estimator TE minus PBO of −0.813 and −0.689 BM/day for 250 mg and 500 mg tid, respectively) over the 12-week double-blind period. At Week 12, declines in BM frequency from baseline were 17%, 29%, and 35% on PBO, TE 250 mg tid, and TE 500 mg tid, respectively. The proportions of patients with durable response (at least 30% reduction in BM frequency for 50% of the time on study) were 20%, 44% and 42% on PBO, TE 250 mg tid and TE 500 mg tid, respectively (p 0.040 for both TE doses vs. PBO). At Week 12, u5-HIAA levels on TE compared to PBO were reduced by 30.1 mg/24 hours and 33.8 mg/24 hours in the TE 250 mg tid and 500 mg tid, respectively (baseline u5-HIAA 87.6 mg/24 hours; p < 0.001 for both dosages). Reductions in flushing and abdominal pain were not statistically significant. TE was generally safe and well tolerated. Events of depression were reported in 3, 2, and 6 patients on PBO, TE 250, mg tid and TE 500 mg tid, respectively; most events were mild or moderate and resolved while continuing therapy. The proportions of patients with treatment-emergent adverse events (AEs), serious AEs, and discontinuation due to AEs were similar in all 3 treatment arms. 87% of ran- domized patients continued onto open-label treatment with TE 500 mg tid. Conclusions: Telotristat etiprate provided statistically significant and clinically meaningful reductions in BM frequency and represents a promising new class of treatment for patients who have metastatic NETs with CS not controlled by standard of care SSA therapy. No conflict of interest.