Long-Term Safety Experience with Telotristat Ethyl Across Five Clinical Studies in Patients with Carcinoid Syndrome

Lowell B. Anthony; Matthew H. Kulke; Martyn E. Caplin; Emily Bergsland; Kjell Öberg; Marianne Pavel; Dieter Hörsch; Richard R.P. Warner; Thomas M. O'Dorisio; Joseph S. Dillon; Pablo Lapuerta; Kenneth Kassler-Taub; Wenjun Jiang

doi:10.1634/theoncologist.2018-0236

Long-Term Safety Experience with Telotristat Ethyl Across Five Clinical Studies in Patients with Carcinoid Syndrome

Lowell B. Anthony, Matthew H. Kulke, Martyn E. Caplin, Emily Bergsland, Kjell Öberg, Marianne Pavel, Dieter Hörsch, Richard R.P. Warner, Thomas M. O'Dorisio, Joseph S. Dillon, Pablo Lapuerta, Kenneth Kassler-Taub, Wenjun Jiang

Research output: Contribution to journal › Article › peer-review

9 Scopus citations

Abstract

Background: Patients with neuroendocrine tumors (NETs) and carcinoid syndrome experience considerable morbidity and mortality; carcinoid syndrome may be associated with shorter survival. Carcinoid syndrome is linked to tumoral secretion of serotonin and other bioactive substances. The subsequent debilitating diarrhea and urgency to defecate pose significant health risks. In previous studies, telotristat ethyl, a tryptophan hydroxylase inhibitor, was effective and well tolerated in treating carcinoid syndrome diarrhea. We present pooled safety data from five clinical trials with telotristat ethyl in patients with carcinoid syndrome. Subjects, Materials, and Methods: Adverse events reported during telotristat ethyl treatment were pooled from two phase II and three phase III clinical trials in 239 patients with carcinoid syndrome. Long-term safety of telotristat ethyl and causes of hospitalization and death were reviewed; overall survival was estimated. Results: Mean (median; range) duration of exposure and follow-up was 1.3 years (1.1 years; 1 week to 5.7 years), with 309 total patient-years of exposure. Leading causes of hospitalization were gastrointestinal disorders or were related to the underlying tumor and related treatment. Survival estimates at 1, 2, and 3 years were 93%, 88%, and 77%. Nearly all deaths were due to progression or complication of the underlying disease; none were attributable to telotristat ethyl. There was one death in year 4. Conclusion: Based on long-term safety data, telotristat ethyl is well tolerated and has a favorable long-term safety profile in patients with carcinoid syndrome. Implications for Practice: Carcinoid syndrome can cause persistent diarrhea, even in patients treated with somatostatin analogs. Across five clinical trials in patients with carcinoid syndrome, telotristat ethyl has been well tolerated and efficacious, providing clinicians with a new approach to help control carcinoid syndrome diarrhea, in addition to somatostatin analog therapy. By reducing the stool frequency in patients with carcinoid syndrome whose diarrhea is refractory to anticholinergics, such as loperamide and atropine/diphenoxylate, and somatostatin analog dose escalation, improvement in quality of life becomes an achievable goal.

Original language	English
Pages (from-to)	e662-e670
Journal	Oncologist
Volume	24
Issue number	8
DOIs	https://doi.org/10.1634/theoncologist.2018-0236
State	Published - 2019

Bibliographical note

Funding Information:
We thank the patients and investigators for participating in the studies. We thank James Banigan, Ph.D. (Chameleon Communications International, with funding provided by Lexicon Pharmaceuticals, Inc.), for medical editorial assistance with this manuscript. We thank the following Lexicon employees: Kristi A. Boehm, M.S., E.L.S., for her assistance with figure preparation, text formatting, and editing of this manuscript; Linda Law, M.D., M.B.A., for study design; Karie Arnold, B.S., and Ernest Wang, B.S., for study monitoring; and Nam Wommack, B.S.N., M.P.H., for data management. Lastly, we would like to thank the team at INC Research (Raleigh, NC) for study conduct, monitoring, analysis, and reporting. We thank Ipsen Pharmaceuticals, Inc., a partner of Lexicon Pharmaceuticals, Inc., for review of this manuscript for medical accuracy. This work was supported by Lexicon Pharmaceuticals, Inc., The Woodlands, TX. Employees of the company were involved in the study designs; the collection, analysis, and interpretation of data; the writing and review

Funding Information:
We thank the patients and investigators for participating in the studies. We thank James Banigan, Ph.D. (Chameleon Communications International, with funding provided by Lexicon Pharmaceuticals, Inc.), for medical editorial assistance with this manuscript. We thank the following Lexicon employees: Kristi A. Boehm, M.S., E.L.S., for her assistance with figure preparation, text formatting, and editing of this manuscript; Linda Law, M.D., M.B.A., for study design; Karie Arnold, B.S., and Ernest Wang, B.S., for study monitoring; and Nam Wommack, B.S.N., M.P.H., for data management. Lastly, we would like to thank the team at INC Research (Raleigh, NC) for study conduct, monitoring, analysis, and reporting. We thank Ipsen Pharmaceuticals, Inc., a partner of Lexicon Pharmaceuticals, Inc., for review of this manuscript for medical accuracy. This work was supported by Lexicon Pharmaceuticals, Inc., The Woodlands, TX. Employees of the company were involved in the study designs; the collection, analysis, and interpretation of data; the writing and review of the manuscript; and the decision to submit for publication. Selected data have been presented in abstract/poster format at the European Society of Medical Oncology Congress, Madrid, Spain, September 8?12, 2017 (442P). Marianne Pavel is currently affiliated with the Department of Medicine 1, Division of Endocrinology, Friedrich-Alexander-Universit?t Erlangen-N?rnberg, Erlangen, Germany.

Publisher Copyright:
© AlphaMed Press 2019

Keywords

Diarrhea
Malignant carcinoid syndrome
Neuroendocrine tumors
Serotonin
Telotristat ethyl
Tryptophan hydroxylase

ASJC Scopus subject areas

Oncology
Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1634/theoncologist.2018-0236

Cite this

Anthony, L. B., Kulke, M. H., Caplin, M. E., Bergsland, E., Öberg, K., Pavel, M., Hörsch, D., Warner, R. R. P., O'Dorisio, T. M., Dillon, J. S., Lapuerta, P., Kassler-Taub, K., & Jiang, W. (2019). Long-Term Safety Experience with Telotristat Ethyl Across Five Clinical Studies in Patients with Carcinoid Syndrome. Oncologist, 24(8), e662-e670. https://doi.org/10.1634/theoncologist.2018-0236

@article{88a3b63983de4e858fdb09fd34b9ca55,

title = "Long-Term Safety Experience with Telotristat Ethyl Across Five Clinical Studies in Patients with Carcinoid Syndrome",

abstract = "Background: Patients with neuroendocrine tumors (NETs) and carcinoid syndrome experience considerable morbidity and mortality; carcinoid syndrome may be associated with shorter survival. Carcinoid syndrome is linked to tumoral secretion of serotonin and other bioactive substances. The subsequent debilitating diarrhea and urgency to defecate pose significant health risks. In previous studies, telotristat ethyl, a tryptophan hydroxylase inhibitor, was effective and well tolerated in treating carcinoid syndrome diarrhea. We present pooled safety data from five clinical trials with telotristat ethyl in patients with carcinoid syndrome. Subjects, Materials, and Methods: Adverse events reported during telotristat ethyl treatment were pooled from two phase II and three phase III clinical trials in 239 patients with carcinoid syndrome. Long-term safety of telotristat ethyl and causes of hospitalization and death were reviewed; overall survival was estimated. Results: Mean (median; range) duration of exposure and follow-up was 1.3 years (1.1 years; 1 week to 5.7 years), with 309 total patient-years of exposure. Leading causes of hospitalization were gastrointestinal disorders or were related to the underlying tumor and related treatment. Survival estimates at 1, 2, and 3 years were 93%, 88%, and 77%. Nearly all deaths were due to progression or complication of the underlying disease; none were attributable to telotristat ethyl. There was one death in year 4. Conclusion: Based on long-term safety data, telotristat ethyl is well tolerated and has a favorable long-term safety profile in patients with carcinoid syndrome. Implications for Practice: Carcinoid syndrome can cause persistent diarrhea, even in patients treated with somatostatin analogs. Across five clinical trials in patients with carcinoid syndrome, telotristat ethyl has been well tolerated and efficacious, providing clinicians with a new approach to help control carcinoid syndrome diarrhea, in addition to somatostatin analog therapy. By reducing the stool frequency in patients with carcinoid syndrome whose diarrhea is refractory to anticholinergics, such as loperamide and atropine/diphenoxylate, and somatostatin analog dose escalation, improvement in quality of life becomes an achievable goal.",

keywords = "Diarrhea, Malignant carcinoid syndrome, Neuroendocrine tumors, Serotonin, Telotristat ethyl, Tryptophan hydroxylase",

author = "Anthony, {Lowell B.} and Kulke, {Matthew H.} and Caplin, {Martyn E.} and Emily Bergsland and Kjell {\"O}berg and Marianne Pavel and Dieter H{\"o}rsch and Warner, {Richard R.P.} and O'Dorisio, {Thomas M.} and Dillon, {Joseph S.} and Pablo Lapuerta and Kenneth Kassler-Taub and Wenjun Jiang",

note = "Funding Information: We thank the patients and investigators for participating in the studies. We thank James Banigan, Ph.D. (Chameleon Communications International, with funding provided by Lexicon Pharmaceuticals, Inc.), for medical editorial assistance with this manuscript. We thank the following Lexicon employees: Kristi A. Boehm, M.S., E.L.S., for her assistance with figure preparation, text formatting, and editing of this manuscript; Linda Law, M.D., M.B.A., for study design; Karie Arnold, B.S., and Ernest Wang, B.S., for study monitoring; and Nam Wommack, B.S.N., M.P.H., for data management. Lastly, we would like to thank the team at INC Research (Raleigh, NC) for study conduct, monitoring, analysis, and reporting. We thank Ipsen Pharmaceuticals, Inc., a partner of Lexicon Pharmaceuticals, Inc., for review of this manuscript for medical accuracy. This work was supported by Lexicon Pharmaceuticals, Inc., The Woodlands, TX. Employees of the company were involved in the study designs; the collection, analysis, and interpretation of data; the writing and review Funding Information: We thank the patients and investigators for participating in the studies. We thank James Banigan, Ph.D. (Chameleon Communications International, with funding provided by Lexicon Pharmaceuticals, Inc.), for medical editorial assistance with this manuscript. We thank the following Lexicon employees: Kristi A. Boehm, M.S., E.L.S., for her assistance with figure preparation, text formatting, and editing of this manuscript; Linda Law, M.D., M.B.A., for study design; Karie Arnold, B.S., and Ernest Wang, B.S., for study monitoring; and Nam Wommack, B.S.N., M.P.H., for data management. Lastly, we would like to thank the team at INC Research (Raleigh, NC) for study conduct, monitoring, analysis, and reporting. We thank Ipsen Pharmaceuticals, Inc., a partner of Lexicon Pharmaceuticals, Inc., for review of this manuscript for medical accuracy. This work was supported by Lexicon Pharmaceuticals, Inc., The Woodlands, TX. Employees of the company were involved in the study designs; the collection, analysis, and interpretation of data; the writing and review of the manuscript; and the decision to submit for publication. Selected data have been presented in abstract/poster format at the European Society of Medical Oncology Congress, Madrid, Spain, September 8?12, 2017 (442P). Marianne Pavel is currently affiliated with the Department of Medicine 1, Division of Endocrinology, Friedrich-Alexander-Universit?t Erlangen-N?rnberg, Erlangen, Germany. Publisher Copyright: {\textcopyright} AlphaMed Press 2019",

year = "2019",

doi = "10.1634/theoncologist.2018-0236",

language = "English",

volume = "24",

pages = "e662--e670",

number = "8",

}

Anthony, LB, Kulke, MH, Caplin, ME, Bergsland, E, Öberg, K, Pavel, M, Hörsch, D, Warner, RRP, O'Dorisio, TM, Dillon, JS, Lapuerta, P, Kassler-Taub, K & Jiang, W 2019, 'Long-Term Safety Experience with Telotristat Ethyl Across Five Clinical Studies in Patients with Carcinoid Syndrome', Oncologist, vol. 24, no. 8, pp. e662-e670. https://doi.org/10.1634/theoncologist.2018-0236

TY - JOUR

T1 - Long-Term Safety Experience with Telotristat Ethyl Across Five Clinical Studies in Patients with Carcinoid Syndrome

AU - Anthony, Lowell B.

AU - Kulke, Matthew H.

AU - Caplin, Martyn E.

AU - Bergsland, Emily

AU - Öberg, Kjell

AU - Pavel, Marianne

AU - Hörsch, Dieter

AU - Warner, Richard R.P.

AU - O'Dorisio, Thomas M.

AU - Dillon, Joseph S.

AU - Lapuerta, Pablo

AU - Kassler-Taub, Kenneth

AU - Jiang, Wenjun

N1 - Funding Information: We thank the patients and investigators for participating in the studies. We thank James Banigan, Ph.D. (Chameleon Communications International, with funding provided by Lexicon Pharmaceuticals, Inc.), for medical editorial assistance with this manuscript. We thank the following Lexicon employees: Kristi A. Boehm, M.S., E.L.S., for her assistance with figure preparation, text formatting, and editing of this manuscript; Linda Law, M.D., M.B.A., for study design; Karie Arnold, B.S., and Ernest Wang, B.S., for study monitoring; and Nam Wommack, B.S.N., M.P.H., for data management. Lastly, we would like to thank the team at INC Research (Raleigh, NC) for study conduct, monitoring, analysis, and reporting. We thank Ipsen Pharmaceuticals, Inc., a partner of Lexicon Pharmaceuticals, Inc., for review of this manuscript for medical accuracy. This work was supported by Lexicon Pharmaceuticals, Inc., The Woodlands, TX. Employees of the company were involved in the study designs; the collection, analysis, and interpretation of data; the writing and review Funding Information: We thank the patients and investigators for participating in the studies. We thank James Banigan, Ph.D. (Chameleon Communications International, with funding provided by Lexicon Pharmaceuticals, Inc.), for medical editorial assistance with this manuscript. We thank the following Lexicon employees: Kristi A. Boehm, M.S., E.L.S., for her assistance with figure preparation, text formatting, and editing of this manuscript; Linda Law, M.D., M.B.A., for study design; Karie Arnold, B.S., and Ernest Wang, B.S., for study monitoring; and Nam Wommack, B.S.N., M.P.H., for data management. Lastly, we would like to thank the team at INC Research (Raleigh, NC) for study conduct, monitoring, analysis, and reporting. We thank Ipsen Pharmaceuticals, Inc., a partner of Lexicon Pharmaceuticals, Inc., for review of this manuscript for medical accuracy. This work was supported by Lexicon Pharmaceuticals, Inc., The Woodlands, TX. Employees of the company were involved in the study designs; the collection, analysis, and interpretation of data; the writing and review of the manuscript; and the decision to submit for publication. Selected data have been presented in abstract/poster format at the European Society of Medical Oncology Congress, Madrid, Spain, September 8?12, 2017 (442P). Marianne Pavel is currently affiliated with the Department of Medicine 1, Division of Endocrinology, Friedrich-Alexander-Universit?t Erlangen-N?rnberg, Erlangen, Germany. Publisher Copyright: © AlphaMed Press 2019

PY - 2019

Y1 - 2019

N2 - Background: Patients with neuroendocrine tumors (NETs) and carcinoid syndrome experience considerable morbidity and mortality; carcinoid syndrome may be associated with shorter survival. Carcinoid syndrome is linked to tumoral secretion of serotonin and other bioactive substances. The subsequent debilitating diarrhea and urgency to defecate pose significant health risks. In previous studies, telotristat ethyl, a tryptophan hydroxylase inhibitor, was effective and well tolerated in treating carcinoid syndrome diarrhea. We present pooled safety data from five clinical trials with telotristat ethyl in patients with carcinoid syndrome. Subjects, Materials, and Methods: Adverse events reported during telotristat ethyl treatment were pooled from two phase II and three phase III clinical trials in 239 patients with carcinoid syndrome. Long-term safety of telotristat ethyl and causes of hospitalization and death were reviewed; overall survival was estimated. Results: Mean (median; range) duration of exposure and follow-up was 1.3 years (1.1 years; 1 week to 5.7 years), with 309 total patient-years of exposure. Leading causes of hospitalization were gastrointestinal disorders or were related to the underlying tumor and related treatment. Survival estimates at 1, 2, and 3 years were 93%, 88%, and 77%. Nearly all deaths were due to progression or complication of the underlying disease; none were attributable to telotristat ethyl. There was one death in year 4. Conclusion: Based on long-term safety data, telotristat ethyl is well tolerated and has a favorable long-term safety profile in patients with carcinoid syndrome. Implications for Practice: Carcinoid syndrome can cause persistent diarrhea, even in patients treated with somatostatin analogs. Across five clinical trials in patients with carcinoid syndrome, telotristat ethyl has been well tolerated and efficacious, providing clinicians with a new approach to help control carcinoid syndrome diarrhea, in addition to somatostatin analog therapy. By reducing the stool frequency in patients with carcinoid syndrome whose diarrhea is refractory to anticholinergics, such as loperamide and atropine/diphenoxylate, and somatostatin analog dose escalation, improvement in quality of life becomes an achievable goal.

AB - Background: Patients with neuroendocrine tumors (NETs) and carcinoid syndrome experience considerable morbidity and mortality; carcinoid syndrome may be associated with shorter survival. Carcinoid syndrome is linked to tumoral secretion of serotonin and other bioactive substances. The subsequent debilitating diarrhea and urgency to defecate pose significant health risks. In previous studies, telotristat ethyl, a tryptophan hydroxylase inhibitor, was effective and well tolerated in treating carcinoid syndrome diarrhea. We present pooled safety data from five clinical trials with telotristat ethyl in patients with carcinoid syndrome. Subjects, Materials, and Methods: Adverse events reported during telotristat ethyl treatment were pooled from two phase II and three phase III clinical trials in 239 patients with carcinoid syndrome. Long-term safety of telotristat ethyl and causes of hospitalization and death were reviewed; overall survival was estimated. Results: Mean (median; range) duration of exposure and follow-up was 1.3 years (1.1 years; 1 week to 5.7 years), with 309 total patient-years of exposure. Leading causes of hospitalization were gastrointestinal disorders or were related to the underlying tumor and related treatment. Survival estimates at 1, 2, and 3 years were 93%, 88%, and 77%. Nearly all deaths were due to progression or complication of the underlying disease; none were attributable to telotristat ethyl. There was one death in year 4. Conclusion: Based on long-term safety data, telotristat ethyl is well tolerated and has a favorable long-term safety profile in patients with carcinoid syndrome. Implications for Practice: Carcinoid syndrome can cause persistent diarrhea, even in patients treated with somatostatin analogs. Across five clinical trials in patients with carcinoid syndrome, telotristat ethyl has been well tolerated and efficacious, providing clinicians with a new approach to help control carcinoid syndrome diarrhea, in addition to somatostatin analog therapy. By reducing the stool frequency in patients with carcinoid syndrome whose diarrhea is refractory to anticholinergics, such as loperamide and atropine/diphenoxylate, and somatostatin analog dose escalation, improvement in quality of life becomes an achievable goal.

KW - Diarrhea

KW - Malignant carcinoid syndrome

KW - Neuroendocrine tumors

KW - Serotonin

KW - Telotristat ethyl

KW - Tryptophan hydroxylase

UR - http://www.scopus.com/inward/record.url?scp=85060148656&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85060148656&partnerID=8YFLogxK

U2 - 10.1634/theoncologist.2018-0236

DO - 10.1634/theoncologist.2018-0236

M3 - Article

C2 - 30651397

AN - SCOPUS:85060148656

SN - 1083-7159

VL - 24

SP - e662-e670

JO - Oncologist

JF - Oncologist

IS - 8

ER -

Long-Term Safety Experience with Telotristat Ethyl Across Five Clinical Studies in Patients with Carcinoid Syndrome

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this