Clinical Therapeutics/Volume 40, Number 6, 2018 Changes in Weight Associated With Telotristat Ethyl in the Treatment of Carcinoid Syndrome Martin O. Weickert, MD1; Gregory Kaltsas, MD1; Dieter Ho¨rsch, MD, PhD2; Pablo Lapuerta, MD3; Marianne Pavel, MD4,5; Juan W. Valle, MD6; Martyn E. Caplin, MD7; Emily Bergsland, MD8; Pamela L. Kunz, MD9; Lowell B. Anthony, MD10; Enrique Grande, MD11; Kjell O¨ berg, MD12; Staffan Welin, MD12; Catherine Lombard-Bohas, MD13; John K. Ramage, MD14; Ashwin Kittur, MSPH, MBA3; Qi M. Yang, PhD3; and Matthew H. Kulke, MD15 1The ARDEN NET Centre, ENETS Centre of Excellence, University Hospitals Coventry and Warwickshire National Health Service Trust, Coventry, United Kingdom; 2Zentralklinik Bad Berka, Bad Berka, Germany; 3Lexicon Pharmaceuticals Inc, The Woodlands, Texas; 4Charite´-Universita¨tsmedizin, Berlin, Germany; 5Friedrich-Alexander-Universita¨t Erlangen-Nu¨rnberg, Erlangen, Germany; 6University of Manchester/The Christie National Health Service Foundation Trust, Manchester, United Kingdom; 7Neuroendocrine Tumour Unit, European Neuroendocrine Tumor Society Centre of Excellence, Royal Free Hospital, London, United Kingdom; 8University of California, San Francisco, San Francisco, California; 9Stanford University School of Medicine, Stanford, California; 10University of Kentucky, Lexington, Kentucky; 11MD Anderson International Cancer Center, Madrid, Spain; 12Uppsala University Hospital, Uppsala, Sweden; 13Hoˆpital Edouard Herriot, Hospices Civils de Lyon, Lyon, France; 14King’s Health Partners European Neuroendocrine Tumor Society Centre of Excellence, King’s College Hospital, London, United Kingdom; and 15Dana-Farber Cancer Institute, Boston, Massachusetts ABSTRACT (17.1%) taking telotristat ethyl 250 mg TID, and 13 Purpose: In the placebo-controlled Phase III TELE- of 40 (32.5%) taking telotristat ethyl 500 mg TID (P ¼ STAR (Telotristat Etiprate for Somatostatin Analogue 0.0017) at week 12. Weight loss ≥3% was observed in Not Adequately Controlled Carcinoid Syndrome) 5 of 39 patients (12.8%) taking placebo TID, 4 of 41 trial, the oral tryptophan hydroxylase inhibitor telo- (9.8%) taking telotristat ethyl 250 mg TID, and 6 of 40 tristat ethyl significantly reduced bowel movement (15.0%) taking telotristat ethyl 500 mg TID (P ¼ 0.77). (BM) frequency during a 12-week, double-blind treat- Biochemical and metabolic parameters of serum albu- ment period in 135 patients with metastatic neuro- min and cholesterol significantly increased (P ¼ 0.02 endocrine tumors with carcinoid syndrome and ≥4 and P ¼ 0.001, respectively) in patients gaining weight BMs per day. Patients (mean [SD] age, 63.5 [8.9] and decreased in patients who lost weight, suggesting years; mean [SD] body mass index, 24.9 [4.9] kg/m2) an improvement in overall nutritional status. received placebo, telotristat ethyl 250 mg, or telotri- Implications: Up to 32.5% of patients treated with stat ethyl 500 mg 3 times per day (TID) in addition to telotristat ethyl experienced significant, dose-depend- somatostatin analogue therapy. Weight loss is asso- ent weight gain, associated with reduced diarrhea ciated with uncontrolled carcinoid syndrome and may severity and improved biochemical and metabolic be associated with reduced survival. Methods: Assessment of the occurrence of weight change ≥3% at week 12 was prespecified in the Accepted for publication April 10, 2018. statistical analysis plan. https://doi.org/10.1016/j.clinthera.2018.04.006 0149-2918/$ - see front matter Findings: In 120 patients with weight data avail- & ≥ 2018 The Authors. Published by Elsevier HS Journals, Inc. This is an able, weight gain 3% was observed in 2 of 39 open access article under the CC BY-NC-ND license patients (5.1%) taking placebo TID, 7 of 41 (http://creativecommons.org/licenses/by-nc-nd/4.0/). 952 Volume 40 Number 6 M.O. Weickert et al. parameters. Improved nutritional status could be an history of carcinoid syndrome with at least 4 BMs per additional aspect of telotristat ethyl efficacy among day, and were receiving treatment with long-acting patients with functioning metastatic neuroendocrine SSAs for ≥3 months before enrollment. Detailed tumors. ClinicalTrials.gov identifier: NCT01677910. inclusion and exclusion criteria have been published (Clin Ther. 2018;40:952–962) & 2018 The Authors. previously.1 Published by Elsevier HS Journals, Inc. (Clin Ther. 2018;40:952–962) & 2018 The Authors. Published by Study Design and Treatment Elsevier HS Journals, Inc. Eligible patients entered a screening period of 3 or Key words: carcinoid syndrome, carcinoid syn- 4 weeks, depending on their SSA dose schedule, to drome diarrhea, malnutrition, neuroendocrine tumor, establish baseline symptoms. Patients were randomly telotristat ethyl, weight. assigned 1:1:1 to orally receive placebo 3 times per day (TID), telotristat ethyl 250 mg TID, or telotristat ethyl 500 mg TID for the 12-week double-blind treatment period. Treatment with SSAs was contin- INTRODUCTION ued. Rescue use of short-acting octreotide and anti- Telotristat ethyl is used to treat patients with neuro- diarrheal agents was unrestricted, but there was no endocrine tumors (NETs) with carcinoid syndrome significant difference in use among the treatment not adequately controlled by somatostatin analogs arms.1 Downward dose adjustment of telotristat (SSAs).1 Telotristat ethyl is an inhibitor of trypto- ethyl was not allowed during the double-blind phan hydroxylase, the rate-limiting enzyme in treatment period. The study was approved by the serotonin synthesis that converts tryptophan to 5- respective institutional review boards or ethics hydroxytryptophan, which is subsequently converted committees at the participating centers. All patients to serotonin. Treatment with telotristat ethyl gave written informed consent. The study complied significantly reduces both urinary 5-hydroxyindole with the ethical principles of the Declaration of acetic acid (u5-HIAA) concentrations and bowel 6 – Helsinki and with Good Clinical Practice guidelines. movement (BM) frequency compared with placebo.1 3 The study drug dosage form consisted of white- Telotristat ethyl, in combination with SSA therapy, was coated, debossed oval tablets that contained 250 mg recently approved for adults in the United States and of telotristat ethyl or matching inactive placebo of Europe for the treatment of carcinoid syndrome diar- microcrystalline cellulose. There was no taste reported rhea inadequately controlled by SSAs.4,5 for the tablets. During the dose-escalation phases, the Generally, weight loss is a manifestation of advanced assigned study drug was provided in 8-day blister malignancy and is evident in patients with carcinoid packs that contained 6 columns and 8 rows for a total syndrome, who may experience profound diarrhea. of 48 tablets. After the dose-escalation phase, patients Incidence of weight gain was added as an exploratory received their assigned study drug in 100-mL high- analysis in the TELESTAR (Telotristat Etiprate for density polyethylene bottles with child-resistant poly- Somatostatin Analogue Not Adequately Controlled propylene screwcaps and heat-induction seal liners. Carcinoid Syndrome) study to determine the effects of There was no official assessment of the success of telotristat ethyl on weight. We report dose-dependent matching performed. effects of treatment with telotristat ethyl on changes in Prior medical histories (before enrollment) were weight, metabolic parameters, and patient-reported out- reviewed relating to weight gain, weight loss, and comes during the 12-week double-blind treatment nutritional status by searching for relevant conditions period of the Phase III TELESTAR clinical trial. among the Medical Dictionary for Regulatory Activ- ities (MedDRA) System Organ Classes of Gastro- PATIENTS AND METHODS intestinal Disorders, General and Nutritional Patients Disorders, and Metabolic Parameters. The potential The TELESTAR study cohort has been described associations of weight change with BM frequency in detail previously.1 Eligible patients were at least reduction and changes in u5-HIAA concentrations 18 years of age, had a histopathologically confirmed were examined. Patient-reported outcomes were diagnosis of a metastatic NET, had a documented examined with the European Organisation for June 2018 953 Clinical Therapeutics Research and Treatment of Cancer Quality of Life included Kruskal-Wallis tests and Fisher exact tests Questionnaire–Core 30 (EORTC QLQ-C30) for items to investigate differences among groups. Cochran- that describe a global assessment or aspects that Armitage tests were applied to investigate for trends relate directly or indirectly to gastrointestinal function. in the incidence of weight gain in the placebo, Selected metabolic parameters (serum cholesterol, telotristat ethyl 250 mg TID, and telotristat ethyl 500 triglycerides, and albumin) and serum creatinine were mg TID treatment groups; ANOVA was applied to test compared among patients in the categories of weight for changes in metabolic markers among patients with gain, stable weight, and weight loss. weight gain, stable weight, and weight loss. A threshold The incidences of serious adverse events, discontin- of 3% weight change was assumed to be clinically uation attributable to adverse events, and death were relevant and prespecified for the analyses based on the examined, along with the types of adverse events assumption that this degree of weight change would be experienced, among patients in the categories of weight achievable