Safety and Efficacy of Telotristat Ethyl Plus First-Line Chemotherapy in Patients With Advanced BTC: A Phase 2, Open-Label Study

March 2024, Vol 5, No 1
Portrait of Richard Kim, MD

Richard Kim, MD

Biliary tract cancers (BTCs) are a group of malignancies that arise from the epithelium of the biliary tract. Unresectable BTC is associated with a poor prognosis, with <35% of cases amenable to surgical resection and a relapse rate ranging from 46% to 61%.

Telotristat ethyl, a tryptophan hydroxylase-1 inhibitor, reduces the production of serotonin and enhances the antiproliferative effects of cisplatin and gemcitabine chemotherapy in cancer cells, according to preclinical models of cholangiocarcinoma.1-3

The multicenter, open-label, phase 2 study (NCT03790111) presented at ASCO GI by Richard D. Kim, MD, assessed the safety and efficacy of telotristat ethyl plus first-line treatment (a combination of chemotherapy of cisplatin plus gemcitabine) in patients with unresectable, locally advanced, recurrent, or metastatic BTC.

Patients were enrolled from March 6, 2019, to January 28, 2021. They were included if they were aged ≥18 years; had histopathologically or cytologically confirmed, unresectable, locally advanced, recurrent, or metastatic BTC; had no prior tumor-directed therapy in the locally advanced, unresectable, or metastatic setting; had measurable disease defined by the RECIST guidelines (version 1.1); and had an Eastern Cooperative Oncology Group performance status of 0 or 1.

On day 1, patients received oral gemcitabine (1000 mg/m2) and cisplatin (25 mg/m2) with telotristat ethyl (250 mg) 3 times daily for 7 days.

After that, patients received telotristat ethyl (500 mg) 3 times daily continuously, plus gemcitabine and cisplatin therapy on days 1 and 8 of each 21-day cycle.

This study included multiple stages: stage 1 enrolled 20 patients with a safety run-in cohort of the first 6 patients to monitor the safety and tolerability of telotristat ethyl plus gemcitabine and cisplatin treatment for 21 days. Stage 2, if achievable, would consist of 33 patients if no significant/unresolved grade ≥3 toxicities related to the study drug occurred in stage 1.

The primary endpoint was progression-free survival (PFS) at 6 months. The study was successful if ≥34 patients (≥60%) were alive and progression-free at 6 months. Key secondary endpoints included disease control rate, overall response rate, median overall survival, and change from baseline in plasma 5-hydroxyindoleacetic acid (5-HIAA).

A total of 53 patients completed enrollment (stage 1, 20; stage 2, 33) and received at least 1 dose of the study drug. Patients had a median age of 66 years, and 62.3% were female. The mean baseline plasma 5-HIAA level was 11.1 µg/L of solution. The 6-month PFS rate was 22.6%. Over 6 months, plasma 5-HIAA levels reduced to 1.74 µg/L.

Subgroup analysis yielded similar progression rates relative to baseline plasma 5-HIAA levels. All progression-free patients reported a decrease in plasma 5-HIAA levels at 6 months.

All patients reported at least 1 treatment-emergent adverse event (TEAE); 75.5% of patients experienced a TEAE related to telotristat ethyl administration.

A total of 86.8% of patients experienced a grade 3/4 TEAE, and 28.3% had a grade 3/4 TEAE related to telotristat ethyl. The most common TEAE (≥10%) related to the study drug was constipation, which occurred in 23 people, or 43% of patients.

A total of 5.7% of patients experienced a TEAE that resulted in discontinuation from the study, and 5.7% of patients experienced a TEAE that resulted in death. However, no deaths were considered related to telotristat ethyl administration.

The study did not meet its prespecified primary endpoint of PFS at 6 months; therefore, it was terminated prematurely before the follow-up period was finished. Telotristat ethyl did not provide additional benefit to cisplatin plus gemcitabine chemotherapy. Additionally, serotonin is not likely to be a key driver of BTC based on subgroup analysis.

There were no additional safety signals reported with telotristat ethyl when combined with chemotherapy, and the toxicity profile was similar to cisplatin plus gemcitabine chemotherapy as an independent therapy.4


  1. Zhao DY, Lim KH. Current biologics for treatment of biliary tract cancers. J Gastrointest Oncol. 2017;8(3):430-440.
  2. Rangarajan K, Simmons G, Manas D, et al. Systemic adjuvant chemotherapy for cholangiocarcinoma surgery: a systematic review and meta-analysis. Eur J Surg Oncol. 2020;46(4 pt. a):684-693.
  3. Darman L, Schwarz MA, Schwarz R, et al. Abstract 480: enhancing chemotherapy response by telotristat ethyl, an inhibitor of tryptophan hydroxylase involved in serotonin synthesis, in cholangiocarcinoma. Cancer Res. 2023;83(suppl 7):480.
  4. Richard DK, Joseph-Ridge N, Du J, et al. A phase 2, open-label, safety and efficacy study of telotristat ethyl plus first-line chemotherapy in patients with advanced biliary tract cancer. San Fransico, CA, & online: presented at ASCO Gastrointestinal Cancers Symposium; January 18-20, 2024: poster B17.

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