Integrated placebo-controlled safety analysis from clinical studies of telotristat ethyl for the treatment of carcinoid syndrome

Date

10 Oct 2016

Session

Endocrine and neuroendocrine tumours

Presenters

Matthew Kulke

Citation

Annals of Oncology (2016) 27 (6): 136-148. 10.1093/annonc/mdw369

Authors

M. Kulke1, D. Hörsch2, M. Caplin3, L. Anthony4, E. Bergsland5, K. Oberg6, S. Welin7, R. Warner8, C. Lombard Bohas9, P.L. Kunz10, E. Grande11, J.W. Valle12, P. Lapuerta13, P. Banks13, S. Jackson14, W. Jiang13, T. Biran14, M. Pavel15

Author affiliations

  • 1 Medical Oncology, Dana-Farber Cancer Institute, 02215 - Boston/US
  • 2 Gastroenterology And Endocrinology, Center For Neuroendocrine Tumors Bad Berka, Zentralklinik Bad Berka GmbH, 99437 - Bad Berka/DE
  • 3 Gastroenterology And Neuroendocrine Tumours, Royal Free Hospital School of Medicine, NW3 2QG - London/GB
  • 4 Medical Oncology, University of Kentucky, 40536 - Lexington/US
  • 5 Hematology/oncology, UCSF Helen Diller Family Comprehensive Cancer Center, 94158 - San Francisco/US
  • 6 Dep Of Medical Sciences, Uppsala University Hospital, Uppsala/SE
  • 7 Dep Of Endocrine Oncology, Uppsala University Hospital, SE-751 85 - Uppsala/SE
  • 8 Gastroenterology, Mount SInai Medical College, 10029 - New York/US
  • 9 Medical Oncology, Hopital Edouard Herriot Pav. E bis, 69003 - Lyon/FR
  • 10 Medicine-oncology, Stanford University School of Medicine, Palo Alto/US
  • 11 Medical Oncology, Hospital Universitario Ramon y Cajal, 28031 - Madrid/ES
  • 12 Medical Oncology, University of Manchester / The Christie NHS Foundation Trust, M20 4BX - Manchester/GB
  • 13 Medical Affairs, Lexicon Pharmaceuticals, 77381 - The Woodlands/US
  • 14 Clinical Operations, Lexicon Pharmaceuticals, Inc., 77354 - The Woodlands/US
  • 15 Endocrinology, Charité University Medicine, Berlin/DE
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Background

Telotristat etiprate (TE) is an oral tryptophan hydroxylase inhibitor in development for the treatment of carcinoid syndrome (CS). During the placebo-controlled, 12-week double-blind treatment (DBT) periods of 2 Phase 3 studies, TELESTAR and TELECAST, TE significantly reduced bowel movement (BM) frequency compared to placebo.

Methods

211 patients (pts) with CS were randomly assigned (1:1:1) to placebo or TE 250 mg or 500 mg, each given 3x/day (tid). At entry, pts on stable-dose long-acting somatostatin analog (SSA) therapy had ≥4 (TELESTAR) or

Results

71 pts on placebo and 70 pts each on TE 250 mg or 500 mg tid were analyzed. At entry, 47% of pts were female, all pts had metastatic neuroendocrine tumors with mean disease duration of 7 yrs, mean BM frequency was 5.7 (TELESTAR) and 2.5 (TELECAST) BMs/day, and mean urinary 5-hydroxyindoleacetic acid was 84 mg/day. DBT period completion rates were similar between TE (88%) and placebo (87%) pts, as were incidences of SAEs and treatment withdrawal due to TEAE. Hepatic enzyme elevations were no greater than Drug-Induced Liver Injury Network Grade 1 (mild; on a scale up to 5). Slightly higher rates of nausea, constipation, and depression were reported with TE. There were no serious AESIs related to depression.

Conclusions

Integrated safety analyses of placebo-controlled data support the proposed use of TE for the treatment of CS in patients receiving SSA therapy.

TE
# of pts with: Placebo n = 71 250 mg tid n = 70 500 mg tid n = 70
≥1 TEAE 60 62 63
≥1 SAE 12 8 10
Death 3 1 1
Drug withdrawal due to TEAE 12 15 9
AESIs
- Depression related 5 5 8
- Hepatic enzymes 0 10 8
- Any GI 30 32 32
- Nausea 9 9 16
- Vomiting 5 3 6
- Constipation 2 4 5

Clinical trial identification

TELESTAR: NCT01677910, primary completion date (march 2016) TELECAST: NCT02063659, primary completion date (march 2016)

Legal entity responsible for the study

Lexicon Pharmaceuticals, Inc.

Funding

Lexicon Pharmaceuticals, Inc.

Disclosure

M. Kulke: Conflict of interest: Consulting for Lexicon Pharmaceuticals; No other relationships/conditions/circumstances that present a potential conflict of interest. Dr Kulke reports other from Lexicon Pharmaceuticals, during the conduct of the study.

D. Hörsch: Personal fees and other from Lexicon Pharmaceuticals, Inc, grants, personal fees and other from Novartis Pharma, personal fees and other from Ipsen Pharma, personal fees and other from Pfizer Pharma, outside the submitted work.

M. Caplin: Personal fees from Lexicon, personal fees from Novartis, personal fees from IPSEN, outside the submitted work.

L. Anthony: Grants and personal fees from Lexicon Pharmaceuticals, Inc., during the conduct of the study.

E. Bergsland: Other from Lexicon, during the conduct of the study; other from Novartis, other from Ipsen, outside the submitted work.

R. Warner: Personal fees from Lexicon, personal fees from Novartis, outside the submitted work.

C. Lombard Bohas: Other from Lexicon, during the conduct of the study; other from Novartis, from IPSNE, outside the submitted work.

P.L. Kunz: Grants and personal fees from Lexicon Pharmaceuticals, grants and personal fees from Novartis, outside the submitted work.

E. Grande: Grants from Pfizer, grants from Merck-Serono, personal fees from Lexicon, during the conduct of the study.

J.W. Valle: Grants and personal fees from Ipsen; grants and personal fees from Novartis; and personal fees from Pfizer, outside the submitted work.

P. Lapuerta: Employee of Lexicon Pharmaceuticals during the conduct of the study. I am an employee of Lexicon Pharmaceuticals and have been compensated with salary, stock, and stock options.

P. Banks: Other from Lexicon Pharmaceuticals, outside the submitted work.

S. Jackson, W. Jiang: Employee of Lexicon Pharmaceuticals, Inc.

T. Biran: Employee of Lexicon Pharmaceuticals and have been compensated with salary, stock, and stock options.

M. Pavel: Personal fees from Lexicon, personal fees from Novartis, personal fees from Ipsen, personal fees from Pfizer, outside the submitted work.

All other authors have declared no conflicts of interest.

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