Changes in Weight Associated with Telotristat Ethyl in the Treatment of Carcinoid Syndrome

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

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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 during a 12-week treatment period and was gain, stable weight, and weight loss. In addition, considered unlikely to be caused by chance alone. possible adverse events of the treatment relating to edema, weight loss, and malnutrition were examined. RESULTS Statistical Analysis Baseline Characteristics Statistical analyses were performed using SAS Of 135 randomly assigned patients in the TELE- software, version 9.3 (SAS Institute, Cary, North STAR trial, 120 had available data for inclusion in Carolina). Results are presented as mean (SD). this analysis. A total of 15 patients did not have their A2-tailedP o 0.05 was considered statistically weight measured at baseline (4 patients) or week 12 significant. Assessment of the incidence of weight (13 patients) (2 patients did not have their weight change of ≥3% at week 12 was prespecified in the measured at either time point), so their changes from TELESTAR statistical analysis plan. Posthoc analyses baseline could not be calculated (Supplemental Fig. 1).

Table I. Demographic and patient characteristics at baseline (n ¼ 120).*

≥3% Weight Gain Stable Weight ≥3% Weight Loss † Characteristic (n ¼ 22) (n ¼ 83) (n ¼ 15) P

Age, mean (SD), y 62.4 (11) 63.4 (8.7) 66.3 (7.7) 0.23 Female, % 54.5 44.6 40 0.66 White, % 95.5 88.0 93.3 NC Weight, mean (SD), kg 68.6 (17.6) 73.7 (15.7) 69.0 (16.1) 0.31 BMI, mean (SD), kg/m2 24.2 (5.7) 25.3 (4.6) 24.6 (5.0) 0.47 Treatment with SSA, % Octreotide 63.6 78.3 93.3 0.11 Lanreotide 36.4 21.7 6.7 ‡ u5-HIAA at the ULN or higher, % 27.3 38.6 20.0 0.48

BMI ¼ body mass index; NC ¼ not calculated; SSA ¼ somatostatin analog; u5-HIAA ¼ urinary 5-hydroxyindoleacetic acid; ULN ¼ upper limit of normal. ⁎ Patients are separated into 3 groups according to alteration of their weight during the 12-week study period as those obtaining weight gain, stable weight, or weight loss. † P values refer to the Kruskal-Wallis test of group differences (≥3% weight gain, stable weight, or ≥3% weight loss groups) for continuous variables or Fisher exact test for categorical variables and are descriptive. ‡ The ULN for u5-HIAA is 15 mg per 24 hours.

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Of the 13 patients who had no weight measurement at TID. The occurrence of weight gain across groups was week 12, 9 patients discontinued from the study significantly different among the 3 groups (P ¼ before week 12, 2 patients completed but did not 0.0017) (Figure 1A). There was no significant have their weight measured at week 12, and 2 patients difference among the treatment arms for the did not have their weight measured at baseline or occurrence of weight loss ≥3% (P ¼ 0.77) week 12. During the double-blind treatment period, 5 (Figure 1B). The mean weight gain was patients died (3 in the placebo group and 1 each in the approximately 5% in those classified as having ≥3% telotristat ethyl 250 mg and 500 mg TID groups). weight gain, whereas those with weight loss These patients had no data available at the week 12 experienced a substantial mean loss of 7%. There follow-up visit and therefore could not be categorized was a small treatment effect observed in mean weight with regard to weight change. Some of the patients change (Figure 2). Table III summarizes changes in who discontinued the study because of adverse events weight relative to baseline after the 12-week double- could be categorized: although the adverse event had blind treatment period. its onset during the double-blind treatment period, the discontinuation occurred after the week 12 weight data were collected. Changes in BM Frequencies Baseline characteristics of the patients are presented The mean baseline BM frequency was 5.8 BMs per in Table I and Supplemental Table I. For this analysis, day and was comparable among the groups (weight patients were separated into 3 groups, according to gainers, 6.7 BMs per day; stable weight, 5.5 BMs per occurrence of alteration of their weight during the 12- day; weight losers, 5.3 BMs per day; P ¼ 0.47). week double-blind treatment period as those with Among patients with a weight gain occurrence, ≥3% weight gain, those maintaining stable weight, changes in BM frequency at week 12 were –1.2, or those experiencing ≥3% weight loss. Baseline –1.3, and –2.5 for those treated with placebo (n ¼ characteristics were established on day 1 of the 2), telotristat ethyl 250 mg TID (n ¼ 7), and telotristat double-blind treatment period, the same day as the ethyl 500 mg TID (n ¼ 13), respectively. Overall, first dose of study drug. Baseline u5-HIAA was patients with weight gain (including those in the established during the screening or run-in period, at placebo, telotristat ethyl 250 mg TID, and telotristat least 2 weeks before day 1. ethyl 500 mg TID groups) experienced a reduction in BM frequency at week 12 of –2.0 BMs per day. Medical History Reductions at week 12 were –1.3 and –1.7 BMs per All patients had a history of a histologically con- day for those with stable weight and those with ≥3% firmed, well-differentiated metastatic NETs and a weight loss, respectively. clinical diagnosis of carcinoid syndrome. Patients in the TELESTAR study had been diagnosed with metastatic NETs a mean of 7 years before random- Changes in u5-HIAA Concentrations ization. Additional histories relevant to nutritional Baseline values of u5-HIAA were 142, 45, and 90 status are given in Table II. mg per 24 hours among patients with occurrences of weight gain, stable weight, and weight loss, respec- Duration of Treatment tively, and they were highest in the group of patients The mean duration of treatment exposure during who were weight gainers (P o 0.001). The largest the double-blind treatment period was 12.1, 11.7, and reductions in u5-HIAA were observed in the patients 10.8 weeks among patients with weight gain, stable who experienced weight gain, with an observed 57% weight, and weight loss, respectively. decrease in u5-HIAA levels, although some reductions in u5-HIAA were observed in patients with stable Weight Changes weight (12%) and weight loss (39%) (P ¼ 0.009). Weight gain ≥3% at week 12 was observed in 2 of Mean absolute changes in u5-HIAA among patients 39 patients (5.1%) taking placebo, 7 of 41 patients with weight gain, stable weight, and weight loss at (17.1%) taking telotristat ethyl 250 mg TID, and 13 week 12 were –90, –11, and –36 mg per 24 hours, of 40 patients (32.5%) taking telotristat ethyl 500 mg respectively.

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Table II. Number (percentage) of patients by medical history.*

≥3% Weight Gain Stable Weight ≥3% Weight Loss † Preferred Term (n ¼ 22) (n ¼ 83) (n ¼ 15) P

Diarrhea 21 (95.5) 79 (95.2) 15 (100) 40.99 ‡ Pancreatic insufficiency 5 (22.7) 5 (6.0) 3 (20.0) 0.03 Ascites 1 (4.5) 2 (2.4) 0 0.67 Fatigue 19 (45.5) 17 (20.5) 2 (13.3) 0.05 Peripheral edema 6 (27.3) 8 (9.6) 1 (6.7) 0.09 Generalized edema 0 1 (1.2) 0 40.99 General physical health deterioration 0 1 (1.2) 1 (6.7) 0.27 Asthenia 1 (4.5) 7 (8.4) 0 0.73 Cachexia 2 (9.1) 2 (2.4) 1 (6.7) 0.22 Decreased appetite 1 (4.5) 2 (2.4) 0 0.67 Dehydration 1 (4.5) 0 1 (6.7) 0.09 Previous weight loss 5 (22.7) 6 (7.2) 3 (20.0) 0.053 Obesity 6 (27.3) 1 (1.2) 0 o0.001 Diabetes mellitus (all types) 3 (13.6) 7 (8.4) 0 0.39 Type 2 diabetes mellitus 2 (9.1) 5 (6.0) 0 0.70 Hyperlipidemia 2 (9.1) 8 (9.6) 1 (6.7) 40.99 Hypercholesterolemia 1 (4.5) 8 (9.6) 0 0.57 Hypocalcemia 1 (4.5) 3 (3.6) 0 40.99 Lactose intolerance§ 1 (4.5) 1 (1.2) 1 (6.7) 0.22 Hypovitaminosis 0 2 (2.4) 0 40.99 Vitamin D deficiency 4 (18.2) 6 (7.2) 0 0.13 Vitamin B complex deficiency 1 (4.5) 0 0 0.31 fi 4 Vitamin B6 de ciency 0 1 (1.2) 0 0.99 fi Vitamin B12 de ciency 3 (13.6) 7 (8.4) 0 0.39 Folate deficiency 1 (4.5) 1 (1.2) 0 0.51 Iron deficiency 0 1 (1.2) 0 40.99 Magnesium deficiency 2 (9.1) 0 0 0.047 Dyslipidemia 0 2 (2.4) 0 40.99 Malnutrition 0 2 (2.4) 0 40.99

Changes in Selected Metabolic Parameters marker for dehydration or rehydration or possible Related to Nutritional Status development of edema are presented in Table IV. Changes in metabolic parameters of nutritional Results are presented as changes relative to the status and in serum creatinine concentrations as a baseline and are separated by patients who had

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A 0.6 0.5% 0.5% 40 0.4 P = 0.0017 35 32.5% 0.2 n = 41 n = 40 30 0 n = 39 25 -0.2 3% Weight ≥ 20 17.1% -0.4

15 Mean Change in Weight from Baseline at Week 12 (%) from Baseline at Week -0.6 Gain at Week 12 (%) Gain at Week 10 Patients With -0.7% 5.1% -0.8 5 Placebo Telotristat Telotristat Ethyl Ethyl n = 39 n = 41 n = 40 250 mg TID 500 mg TID 0 Placebo Telotristat Telotristat Ethyl Ethyl 250 mg TID 500 mg TID Figure 2. Mean percent change in weight at week B 12 compared with baseline by treat- 40 ment group.

30 gastrointestinal function. In addition, there was a 25 large numerical difference in Global Health Score for 3% Weight ≥ P = 0.77 patients who had lost weight compared with those 20 15.0% with stable weight or weight gain, and there was a 15 12.8% statistically signiﬁcant difference between the 3 weight

Loss at Week 12 (%) Loss at Week 9.8% 10 change groups. The scores presented in Table V reflect Patients With mean changes from baseline for the double-blind 5 n = 39 n = 41 n = 40 treatment period. Results using the EORTC QLQ- 0 Placebo Telotristat Telotristat C30 in TELESTAR were generally similar among the Ethyl Ethyl 250 mg TID 500 mg TID treatment groups, with the most prominent difference being an improvement in the diarrhea subscale with Figure 1. Occurrence of weight gain (A) and telotristat ethyl compared with placebo. The full weight loss (B) of ≥3% during the results were previously reported.1 double-blind treatment period by A summary of adverse events in relation to the P treatment group. The value refers occurrence of weight gain, weight loss, and nutritional to the Kruskal-Wallis test of group status is presented in Supplemental Tables II and III. differences and is descriptive. The incidence of peripheral edema reported during double-blind treatment was consistent with its report- experienced ≥3% weight gain, who maintained their ing in medical history, before treatment with placebo, weight, or who experienced ≥3% weight loss during telotristat ethyl 250 mg TID, or telotristat ethyl 500 the 12-week study period, as well as by treatment arm. mg TID. There was a higher incidence in the weight gain group (18.2%) than in the weight loss group (6.7%) during treatment (Supplemental Table III), and Patient-reported Outcomes it was more common in the weight gain group For patients who had experienced weight gain (27.3%) than the weight loss group (6.7%) in the during the 12-week study period, more favorable medical history (Table II). patient-reported outcomes were identified as evi- denced by numerically higher scores in the EORTC QLQ-C30 items that related to global status or quality DISCUSSION of life and physical function and numerically lower We provide the first report of the effects of treatment scores for EORTC QLQ-C30 items that related to with telotristat ethyl on occurrences of changes in

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Table III. Mean changes in weight relative to baseline after the 12-week double-blind treatment period.

Weight Change Category* Treatment Group Telotristat Telotristat ≥3% Stable ≥3% Ethyl 250 Ethyl 500 Weight Gain Weight Weight Loss Placebo mg TID mg TID † Category (n ¼ 22) (n ¼ 83) (n ¼ 15) P (n ¼ 39) (n ¼ 41) (n ¼ 40)

Change from baseline 3.3 (1.0) 0.1 (1.1) -4.8 (3.2) o0.001 –0.4 (2.5) 0.3 (2.2) 0.3 (3.3) to week 12, mean (SD), kg Change from baseline 4.9 (1.5) 0.2 (1.5) –7.2 (4.4) o0.001 –0.7 (3.4) 0.5 (3.2) 0.5 (4.8) to week 12, mean (SD), %

⁎ Results are presented separately for patients with neuroendocrine tumors and carcinoid syndrome who had experienced ≥3% weight gain, who maintained their weight, or who experienced ≥3% weight loss during the 12-week double-blind treatment period. † P values refer to Kruskal-Wallis test of group differences (≥3% weight gain, stable weight, or ≥3% weight loss groups) and are descriptive. weight in the Phase III, multicenter, double-blind, reasons (in addition to the cachexia that might be placebo-controlled TELESTAR clinical trial in 120 expected in patients with cancer), which include patients with NETs and carcinoid syndrome. The use chronic loose stools, osmotic diarrhea, and excess of telotristat ethyl in this trial was associated with a secretion of serotonin precursors that stimulate gut significant and clinically meaningful dose-dependent transit and small-bowel motility in functioning tu- – increase in the occurrence of weight increase after 12 mors.10,12 14 Treatment with telotristat ethyl improves – weeks. Furthermore, patients with weight gain had BM frequency and reduces u5-HIAA levels.1 3 In our not only evidence of improved carcinoid syndrome study, u5-HIAA levels decreased by 57% in the group control (reduced BM frequency and reduced u5-HIAA of patients who experienced weight gain, and this levels) but also significant improvement in parameters decrease was significantly more pronounced when of nutritional status associated with positive changes compared with those observed in the groups of in patient-reported outcomes compared with patients patients who had experienced stable weight or weight with stable weight or who had experienced weight loss. It is therefore feasible that the dose-dependent loss. effect of treatment with telotristat ethyl on weight gain Weight loss and malnutrition in patients with observed here in patients with carcinoid syndrome malignant tumors are linked to major negative out- might indeed be explained by reduced small-bowel comes, including excess mortality and morbidity and motility and improved nutrient absorbance via telotri- – higher treatment costs.7 9 Although patients with stat ethyl–related reductions of u5-HIAA levels. NETs typically do not present with major weight loss Although weight loss in patients with carcinoid or acute illness before reaching terminal stages with syndrome could also be, at least in part, related to extensive metastatic involvement or carcinoid heart pancreatic masses, tumor infiltration of the mesentery disease,10 recent studies have found that some degree in midgut NETs, prior abdominal surgery, or treat- of malnutrition (mainly based on assessment of body ment with SSAs,10 treatment with telotristat ethyl mass index o20 kg/m2) is common in patients with would not be expected to influence these factors. In NETs, with reported prevalence between 14% and the group of patients who had experienced weight 25%.10,11 Malnutrition in patients with NETs and loss, treatment with telotristat ethyl also appeared to carcinoid syndrome could be present for distinct improve diarrhea, although to a lesser extent, but it

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Table IV. Mean changes in metabolic and biochemical parameters related to nutritional status between baseline and week 12.*

Weight Change Group Treatment Group Telotristat Telotristat ≥3% Weight Stable ≥3% Weight Ethyl 250 mg Ethyl 500 mg † Parameter Gain Weight Loss P Placebo TID TID

Albumin No. of patients 22 75 11 0.020 37 40 37 Mean (SD), g/L 0.6 (4.1) 0.2 (2.4) –2.5 (3.1) –0.3 (2.9) 0.5 (2.9) 0.1 (3.4) Cholesterol No. of patients 22 77 11 0.001 37 42 37 Mean (SD), 0.4 (0.6) 0.2 (0.6) –0.4 (0.6) –0.2 (0.5) 0.4 (0.5) 0.4 (0.7) mmol/L Creatinine clearance No. of patients 19 62 11 0.239 30 33 34 Mean (SD), 2.2 (18.6) 8.0 (33.5) –1.8 (27.5) 2.8 (28.6) 2.0 (27.4) 8.7 (35.5) mL/min Triglycerides No. of patients 22 75 11 0.586 37 40 37 Mean (SD), 0.3 (0.6) 0.1 (0.6) 0.0 (0.7) 0.0 (0.5) 0.2 (0.6) 0.2 (0.6) mmol/L

⁎ Results are presented separately for 120 patients with neuroendocrine tumors and carcinoid syndrome who had experienced ≥3% weight gain, who maintained their weight, or who experienced ≥3% weight loss during the 12-week double-blind treatment period. † P values refer to Kruskal-Wallis test of group differences (≥3% weight gain, stable weight, or ≥3% weight loss groups) and are descriptive. did not result in an improvement of parameters of edema, and appear to represent some true metabolic nutrition status. The absence of a significant difference improvement. Although the involved mechanisms between the treatment arms in patients who remain to be defined, it appears that patients who experienced weight loss may suggest reduced efficacy had weight gain experienced fewer adverse events in of telotristat ethyl in patients with more rapid disease this study; notably, malnutrition and weight loss are – progression. A possible explanation could be that the associated with negative outcomes.9 11,14 There was control of carcinoid syndrome may help patients gain no clear pattern of increased frequency of edema or weight if they have stable disease, whereas poor cardiac conditions to explain the observed weight gain patient outcomes and adverse events associated in this group. Patients who experienced weight gain with weight loss could be linked to rapid tumor also had improvements in patient-reported outcomes progression. and fewer serious adverse events compared with those Our finding of dose-dependent significant increases with stable weight or weight loss, further supporting of serum cholesterol and albumin concentrations in that the weight gain observed in the telotristat ethyl the telotristat ethyl treatment groups, together with treatment groups was clinically beneficial. unchanged serum creatinine clearance, would suggest The strengths of this study include the design as a that the observed occurrences of weight gain in the randomized, double-blind, placebo-controlled trial telotristat ethyl treatment groups cannot be solely and the large multicenter cohort of well-characterized related to rehydration, or possibly development of patients with NETs and carcinoid syndrome.

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Table V. Outcomes for patients with weight gain, stable weight, or weight loss based on EORTC QLQ-C30 items (n ¼ 120).*

† Outcome ≥ 3% Weight Gain Stable Weight ≥ 3% Weight Loss P

Domains where Higher Values Reﬂect Worsening Appetite loss No. of patients 20 71 14 0.06 Score –7.5 –3.3 4.8 Diarrhea No. of patients 19 70 15 0.27 Score –18.4 –14.3 –7.8 Nausea and vomiting No. of patients 20 70 15 0.09 Score –7.1 –1.9 4.4 Fatigue No. of patients 20 71 15 0.39 Score –5.6 –2.6 2.2 Domains Where Higher Values Reﬂect Improvement Physical function No. of patients 20 71 15 0.08 Score 1.2 0.7 –7.8 Global status or QOL No. of patients 19 70 15 o0.001 Score 4.6 1.9 –20.6

EORTC QLQ-C30 ¼ the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30; QOL ¼ quality of life. ⁎ Relating to global status or QOL, physical function, and items relating to gastrointestinal function. The presented scores reﬂect mean changes from baseline for the 12-week double-blind treatment period. † P values refer to Kruskal-Wallis test of group differences (≥3% weight gain, stable weight, or ≥3% weight loss groups) and are descriptive.

Limitations include the lack of availability of addi- maintaining the health of patients with carcinoid tional markers to assess the nutritional status, such as syndrome. The observation that increased weight food diaries, measures of sarcopenia, or biomarkers of appears to be a protective factor for survival in heart failure, such as serum brain natriuretic peptide. patients with NETs is promising in this context.15 Furthermore, although investigation of the incidence In conclusion, among patients with NETs and of weight gain was prespeciﬁed and added as an carcinoid syndrome, the use of telotristat ethyl in a additional exploratory analysis to the statistical analysis Phase III clinical trial was associated with a signiﬁcant plan of TELESTAR before study completion based on the increase in the occurrence of weight gain. Patients suggestion of regulatory authorities to examine the nutri- with weight gain had evidence of carcinoid syndrome tional status of our patients, it was not a registered control, some positive changes in patient-reported secondary outcome measure of this study. outcomes, improvements in selected parameters Further studies are needed to better understand the of nutritional status, and fewer serious adverse potential mechanisms behind the observed dose- events than patients with stable weight or weight dependent occurrence of weight gain on treatment loss. More research is warranted to understand the with telotristat ethyl and whether telotristat ethyl– mechanisms and potential long-term effect of these induced weight gain has long-term implications for changes.

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ACKNOWLEDGMENTS Hörsch reports personal fees from Lexicon Pharma- We thank the patients and investigators for participat- ceuticals, Inc, and grants and personal fees from Ipsen ing in the study. We thank James Banigan, PhD, of Pharmaceuticals, Inc, during the conduct of the study Chameleon Communications International (with fund- and personal fees from Lexicon Pharmaceuticals, Inc, ing provided by Lexicon Pharmaceuticals, Inc) for and grants and personal fees from Ipsen Pharmaceut- medical editorial assistance with this manuscript. We icals, Inc, Novartis Pharmaceuticals, Inc, and Pfizer thank Louise Davies (NET specialist nurse) and Pharmaceuticals, Inc, outside the submitted work. Dr. Narasimha Murthy (consultant endocrinologist), P. Lapuerta, A. Kittur, and Q.M. Yang are employees University Hospitals Coventry and Warwickshire of Lexicon Pharmaceuticals, Inc, and may have com- National Health Service Trust, for support with the mon stock or may have been granted stock options or study. We thank the following Lexicon employees: other equity incentive awards. M. Pavel reports Karie Arnold, Rosanna Fleming, MS, and Shanna institutional research funding and personal fees from Stanley, RN. We thank the team at INC Research Ipsen and Novartis Pharmaceuticals, as well as per- (Raleigh, North Carolina) for study conduct, monitor- sonal fees from Lexicon Pharmaceuticals, Inc, and ing, analysis, and reporting. Lastly, we thank Ipsen Pfizer, Inc. J.W. Valle reports consulting or advisory Pharmaceuticals, Inc, a partner of Lexicon Pharma- roles with Ipsen and Novartis, participation in a ceuticals, Inc., for review of this manuscript for medical speakers’ bureau with Pfizer and Novartis, and institu- accuracy. M.O. Weickert, K. Öberg, and P. Lapuerta tional research funding from Novartis. M.E. Caplin conceived of and designed the study. M.O. Weickert, reports advisory board/speaker honoraria and/or K. Öberg, P.L. Kunz, J.W. Valle, E. Bergsland, research funding from Lexicon Pharmaceuticals, Inc, M.H. Kulke, C. Lombard-Bohas, E. Grande, M. Pavel, Novartis Pharmaceuticals, and Ipsen Biopharmaceut- D. Hörsch, L.B. Anthony, S. Welin, and J.K. Ramage icals. E. Bergsland reports personal fees from UpTo- provided study materials or patients. M.O. Weickert Date, support for a clinical trial from Novartis, and and Q.M. Yang collected and assembled the data. unpaid advisory boards with Lexicon Pharmaceuti- M.O. Weickert, G. Kaltsas, K. Öberg, P.L. Kunz, cals, Inc, and Ipsen outside the submitted work. P.L. J.W. Valle, E. Bergsland, and M.H. Kulke analyzed Kunz reports grants from Lexicon Pharmaceuticals, and interpreted the data. M.O. Weickert developed the Inc, during the conduct of the study, as well as grants first draft of the manuscript. All authors contributed to from Advanced Accelerator Applications, Dicerna, manuscript writing/critical revision, approved the final Esanex, Genentech, Ipsen, Merck, Novartis, and manuscript, and are accountable for all aspects of the Oxigene and personal fees from Ipsen, Lexicon Phar- work. maceuticals, Inc, and Novartis outside the submitted work. L.B. Anthony reports grants and personal fees from Lexicon Pharmaceuticals, Inc, during the FUNDING SOURCES conduct of the study. K. Öberg reports grants from This work was supported by Lexicon Pharmaceuticals, Novartis and honoraria from Ipsen outside the sub- Inc. Employees of the company were involved in the mitted work. J.K. Ramage reports grants from Ipsen study design; the collection, analysis, and interpretation UK during the conduct of the study and grants from of data; the writing and review of the manuscript; and Novartis Pharmaceuticals outside the submitted work. the decision to submit for publication. M.H. Kulke reports relationships with Lexicon Phar- maceuticals, Inc, Ipsen Bioscience, and Novartis Phar- CONFLICTS OF INTEREST maceuticals. The authors have indicated that they M.O. Weickert reports an advisory role on the NET have no other conflicts of interest regarding the education steering board for Ipsen Biopharmaceuti- content of this article. cals; has NET service support from Ipsen, Novartis, and Pfizer; has research funding from Ipsen and Novartis; and receives travel, accommodations, and SUPPLEMENTARY MATERIAL expenses from Novartis and Ipsen Biopharmaceuti- Supplementary data are available in the online version cals. G. Kaltsas reports grants and personal fees from of this article at https://doi.org/10.1016/j.clinthera. Ipsen Bioscience and Novartis Pharmaceuticals. D. 2018.04.006.

June 2018 961 Clinical Therapeutics

REFERENCES 10. Qureshi SA, Burch N, Druce M, 13. Ter-Minassian M, Chan JA, Hoosh- 1. Kulke MH, Horsch D, Caplin ME, et al. Screening for malnutrition in mand SM, et al. Clinical presenta- et al. Telotristat ethyl, a tryptophan patients with gastro-entero-pancre- tion, recurrence, and survival hydroxylase inhibitor for the treat- atic neuroendocrine tumours: a in patients with neuroendocrine ment of carcinoid syndrome. J Clin cross-sectional study. BMJ Open. tumors: results from a prospective Oncol. 2017;35:14–23. 2016;6:e010765. institutional database. Endocr Relat 2. Kulke MH, O'Dorisio T, Phan A, 11. Maasberg S, Knappe-Drzikova B, Cancer. 2013;20:187–196. et al. Telotristat etiprate, a novel Vonderbeck D, et al. Malnutrition 14. Vinik A, Feliberti E, Perry RR. serotonin synthesis inhibitor, in predicts clinical outcome in patients Carcinoid Tumors. In: De Groot LJ, patients with carcinoid syndrome with neuroendocrine neoplasia. Neu- Chrousos G, Dungan K, editors. and diarrhea not adequately roendocrinology. 2017;104:11–25. Endotext. South Dartmouth (MA): controlled by octreotide. Endocr Relat 12. Dimitriadis GK, Weickert MO, Ran- MDText.com, Inc.; 2000. Cancer. 2014;21:705–714. deva HS, et al. Medical management 15. Glazer ES, Stanko K, Ong ES, 3. Pavel M, Horsch D, Caplin M, et al. of secretory syndromes related to Guerrero MA. Decreased inpatient Telotristat etiprate for carcinoid gastroenteropancreatic neuroendo- mortality in obese patients with syndrome: a single-arm, multicenter crine tumours. Endocr Relat Cancer. abdominal nets. Endocr Pract.2014; trial. J Clin Endocrinol Metab.2015; 2016;23:R423–R436. 20:1309–1314. 100:1511–1519. 4. European Commission. Commission Implementing Decision of 18.9.2017 granting marketing authorisation under Regulation (EC) No 726/ 2004 of the European Parliament and of the Council for "Xermelo - telotristat", an orphan medicinal product for human use. 2017. 5. Lexicon Pharmaceuticals Inc. Xermelo® (telotristat ethyl) [prescribing information]: Lexicon Pharmaceuticals, Inc., The Wood- lands, TX; February 2017. 6. ICH Harmonised Tripartite Guide- line. Guideline for Good Clinical Practice E6(R1). 1996. 7. Barker LA, Gout BS, Crowe TC. Hospital malnutrition: prevalence, identiﬁcation and impact on patients and the healthcare system. Int J Environ Res Public Health. 2011;8: 514–527. 8. de Ulibarri Perez JI, Picon Cesar MJ, Garcia Benavent E, Mancha Alvarez- Estrada A. [Early detection and control of hospital malnutrition]. Nutr Hosp. 2002;17:139–146. 9. Stratton RJ, Hackston A, Longmore D, et al. Malnutrition in hospital outpatients and inpatients: prevalence, concurrent validity and ease of use of the 'malnutrition Address correspondence to: Martin O. Weickert, MD, FRCP, The ARDEN universal screening tool' ('MUST') NET Centre, ENETS Centre of Excellence, University Hospitals Coventry for adults. Br J Nutr. 2004;92: and Warwickshire National Health Service Trust, CV2 2DX, Coventry, 799–808. United Kingdom. E-mail: [email protected]

962 Volume 40 Number 6 M.O. Weickert et al.

SUPPLEMENTARY MATERIAL values and other biomarkers in midgut neuroendo- Supplementary References crine tumors (NETs). Pancreas. 2013;42:405–410.

1. Tellez MR, Mamikunian G, O'Dorisio TM, Vinik AI, Woltering EA. A single fasting plasma 5-HIAA See Supplementary Figure 1 and Supplementary value correlates with 24-hour urinary 5-HIAA Table I–III.

TELESTAR N=135

Placebo Telotristat ethyl 250 mg tid Telotristat ethyl 500 mg tid (n=45) (n=45) (n=45)

Baseline weight collected (n=43) Baseline weight collected (n=44) Baseline weight collected (n=44)

Weight at Week 12 collected (n=40) Weight at Week 12 collected (n=42) Weight at Week 12 collected (n=40) Weight at Week 12 not collected (n=5) Weight at Week 12 not collected (n=3) Weight at Week 12 not collected (n=5) Discontinued prior to Week 12 (n=3) Discontinued prior to Week 12 (n=2) Discontinued prior to Week 12 (n=4) Adverse event (n=3) Adverse event (n=1) Adverse event (n=2) Consent withdrawal (n=0) Consent withdrawal (n=0) Consent withdrawal (n=1) Physician decision (n=0) Physician decision (n=0) Physician decision (n=1) Progressive disease (n=0) Progressive disease (n=1) Progressive disease (n=0)

Included in analysis (n=39) Included in analysis (n=41) Included in analysis (n=40) Excluded from analysis (n=6) Excluded from analysis (n=4) Excluded from analysis (n=5)

Supplementary Figure I. Patient ﬂow diagram.

Supplementary Table I. Demographics and patient characteristics at baseline, by treatment arm.

Placebo Telotristat ethyl 250 mg tid Telotristat ethyl 500 mg tid Characteristic (n ¼ 45) (n ¼ 45) (n ¼ 45)

Mean age, years (SD) 63.3 (8.7) 62.4 (9.1) 64.9 (9.1) Female, % 46.7 53.3 44.4 White, % 88.9 91.1 88.9 Weight, kg (SD)a 70.9 (13.9) 70.1 (14.8) 73.4 (20.0) BMI, kg/m2 (SD)b 25.1 (4.8) 24.3 (4.7) 25.2 (5.4) Treatment with SSA Octreotide, % 66.7 88.9 73.3 Lanreotide, % 33.3 11.1 26.7 u5-HIAA ≤ ULNc, % 26.7 26.7 26.7

BMI ¼ body mass index; SD ¼ standard deviation; SSA ¼ somatostatin analog; tid ¼ 3 times per day; u5-HIAA, urinary 5- hydroxyindoleacetic acid; ULN ¼ upper limit of normal. aFor weight, n ¼ 43, 44, and 44 for placebo, telotristat ethyl 250 mg tid, and telotristat ethyl 500 mg tid, respectively. bFor BMI, n ¼ 38, 41, and 39 for placebo, telotristat ethyl 250 mg tid, and telotristat ethyl 500 mg tid, respectively. cNormal range for u5-HIAA is 0–15 mg per 24 hours.1

June 2018 962.e1 Clinical Therapeutics

Supplementary Table II. Summary of patients with any adverse eventsa.

≥3% weight gain Stable weight ≥3% weight loss Category, n (%) (n ¼ 22) (n ¼ 83) (n ¼ 15)

Any TEAE 17 (77.3%) 73 (88.0%) 15 (100%) Any severe TEAE 0 8 (9.6%) 8 (53.3%) Any serious TEAE 1 (4.5%) 9 (10.8%) 6 (40.0%) Any TEAE leading to study drug discontinuation 0 5 (6.0%) 2 (13.3%) Any TEAE leading to study discontinuationb 0 3 (3.6%) 2 (13.3%) Any TEAE resulting in death 0 0 0

TEAE ¼ treatment-emergent adverse event. aResults are presented separately for patients with neuroendocrine tumors and carcinoid syndrome who had experienced ≥3% weight gain, who maintained their weight, or who experienced ≥ % weight loss during the 12-week study period. bTEAEs leading to study discontinuation were anemia, cardiac arrest, nausea, vomiting, eructation, dyspepsia, chills, fatigue, general health deterioration, dehydration, disease progression (5 patients), sepsis, rash, and increased gamma-glutamyl transferase.

Supplementary Table III. Adverse events reported with onset during the double-blind treatment period and with relation to changes in weight and nutritional status.

≥3% weight gain Stable weight ≥3% weight loss Adverse event, n (%) (n ¼ 22) (n ¼ 83) (n ¼ 15)

Asthenia 0 4 (4.8%) 0 Cachexia 0 0 1 (6.7%) Decreased appetite 0 2 (2.4%) 6 (40.0%) Dehydration 0 1 (1.2%) 1 (6.7%) Diabetes mellitus 0 1 (1.2%) 0 Diarrhea 0 3 (3.6%) 1 (6.7%) Disease progression 0 0 1 (6.7%) Fatigue 0 8 (9.6%) 4 (26.7%) General physical health deterioration 0 1 (1.2%) 1 (6.7%) Iron deﬁciency 0 1 (1.2%) 0 Edema peripheral 4 (18.2%) 2 (2.4%) 1 (6.7%) Performance status decreased 0 0 1 (6.7%) Vitamin D deﬁciency 0 1 (1.2%) 0 Weight decreased 0 0 4 (26.7%)

Results are presented separately for patients with neuroendocrine tumors and carcinoid syndrome who had experienced ≥3% weight gain, who maintained their weight, or who experienced ≥3% weight loss during the 12-week double-blind treatment period.

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