Study of Telotristat Etiprate (LX1606) in Participants With Symptomatic Carcinoid Syndrome

Study Overview
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Brief Summary
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The purpose of the study is to evaluate the safety and tolerability of orally administered telotristat etiprate (LX1606) in participants with symptomatic carcinoid syndrome.

Official Title
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A Phase 2, Open-Label, Multi-Center, Serial Ascending-Dose, Dose-Finding Study to Evaluate the Safety and Tolerability of LX1606 in Subjects With Symptomatic Carcinoid Syndrome

Conditions
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Carcinoid Syndrome

Intervention / Treatment
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* Drug: Telotristat etiprate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males and females, aged 18 and older Biopsy-proven metastatic carcinoid tumor of the gastrointestinal (GI) tract with disease extent confirmed by computed tomography (CT), magnetic resonance imaging (MRI), or radionuclide imaging Symptomatic carcinoid syndrome (≥4 bowel movements per day) Ability to provide written informed consent Exclusion Criteria: ≥ 12 high-volume, watery bowel movements per day Sponsor-unacceptable clinical laboratory values for hematology and liver function tests at screening Karnofsky status ≤70% - unable to care for self Surgery within 60 days prior to screening A history of short bowel syndrome Life expectancy < 12 months History of substance or alcohol abuse within 2 years prior to screening Administration of any investigational drug within 30 days of screening or any therapeutic protein or antibody within 90 days of screening

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Telotristat etiprate - Core Phase<br>Following a 2-week Run-In Period, participants received telotristat etiprate capsules at a starting dose of 150 mg, orally three times daily (TID) for 14 days in the Core Phase. Dose escalations (250 mg, 350 mg, 500 mg) occurred serially every 14 days, up to a maximum dosage of telotristat etiprate 500 mg TID, as guided by specific clinical criteria for dose escalation. Upon completion of 12 weeks of treatment, participants were eligible to receive telotristat etiprate in the optional Open-label Extension Period. | Drug: Telotristat etiprate<br>* Telotristat etiprate capsules orally three times daily.<br>* Other names: LX1606 Hippurate;|
| Experimental: Telotristat etiprate - Extension Period<br>Participants received telotristat etiprate at their highest tolerated dose (250 mg or 500 mg), orally, TID for 124 weeks in the Open-label Extension Period. If neither dose was tolerated participants were discontinued from the study and completed the 2-week Follow-up Visit. | Drug: Telotristat etiprate<br>* Telotristat etiprate capsules orally three times daily.<br>* Other names: LX1606 Hippurate;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Any Treatment Emergent Adverse Events (TEAEs) and Drug-Related TEAEs in the Core Phase | An adverse event (AE) was defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug-related. Treatment-emergent AEs were defined as any AEs reported after the first dose of treatment on Day 1. | Baseline up to Week 12 in the Core Phase | 
| Number of Participants With Any Treatment Emergent Adverse Events (TEAEs) and Drug-Related TEAEs in the Extension Period | An adverse event (AE) was defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug-related. Treatment-emergent AEs were defined as any AEs reported after the first dose of treatment on Day 1. | Up to 124 Weeks in the Extension Period | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Number of Bowel Movements (BMs) | Participants recorded the number of bowel movements in a daily diary. The change from baseline value was calculated as the difference between mean numbers of BMs of the post-baseline interval (Weeks 9 to 12) and baseline. A negative change from baseline indicates improvement. Baseline for the Extension Period was defined as non-missing assessment in Run-in period prior to the first dose of study drug. | Core Phase: Baseline to Weeks 9-12; Extension Period: Baseline to Week 24 | 
| Change From Baseline in Stool Form/Consistency | Participants assessed stool form/consistency in a daily diary using a 6-point scale (0-none, 1-hard, 2-firm, 3-soft, 4-loose, 5-watery). The change from the baseline value was calculated as the difference between a mean score of the post-baseline interval (Weeks 9 to 12) and baseline. 0 indicates the best score and 5 indicates the worst score. A negative change from baseline indicates improvement. Baseline for the Extension Period was defined as non-missing assessment in Run-in period prior to the first dose of study drug. | Core Phase: Baseline to Weeks 9-12; Extension Period: Baseline to Week 24 | 
| Change From Baseline in Percentage of Days With Sensation of Urgency to Defecate | Participants assessed the urgency to defecate using a daily diary response to the following question, Have you felt or experienced a sense of urgency to pass stool today?. The change from the baseline value was calculated as the difference between the mean score (percentage of days) of the post-baseline interval (Weeks 9 to 12) and baseline. Baseline for the Extension Period was defined as non-missing assessment in Run-in period prior to the first dose of study drug. | Core Phase: Baseline to Weeks 9-12; Extension Period: Baseline to Week 24 | 
| Change From Baseline in Sensation/Severity of Nausea Using 100 mm Visual Analog Scale (VAS) | Sensation/severity of nausea was measured using a 100 mm VAS. Participants rated their perception of the sensation/severity of nausea experienced by marking a single vertical line on a VAS scale from 0 to 100 mm, where 0 = No vomiting and 100 = vomiting. The change from the baseline value was calculated as the difference between the mean score of the post-baseline interval (Weeks 9 to 12) and baseline. 0 indicates the best score, 100 indicates the worst score. Baseline for the Extension Period was defined as non-missing assessment in Run-in period prior to the first dose of study drug. | Core Phase: Baseline to Weeks 9-12; Extension Period: Baseline to Week 24 | 
| Number of Participants With an Improvement in Global Assessment of Symptoms Associated With Carcinoid Syndrome | Participants assessed their symptoms using a weekly subjective response to the following question, In the past 7 days, have you had adequate relief of your carcinoid syndrome bowel complaints such as diarrhea, urgent need to have a bowel movement, abdominal pain, or discomfort?. The values for improvement in global assessment of symptoms associated with carcinoid syndrome in the Core Phase were averaged from Weeks 9 to 12. | Core Phase: Weeks 9-12; Extension Period: Week 24 | 
| Change From Baseline in Daily Severity of Abdominal Pain or Discomfort Using 100 mm Visual Analog Scale (VAS) | The severity of abdominal pain was measured using a 100 mm VAS. Participants rated their perception of the sensation/severity of abdominal pain or experienced by marking a single vertical line on a VAS scale from 0 to 100 mm, where 0 = No vomiting and 100 = vomiting. The change from the baseline value was calculated as the difference between the mean score of the post-baseline interval (Weeks 9 to 12) and baseline. 0 indicate the best score, 100 indicates the worst score. Baseline for the Extension Period was defined as non-missing assessment in Run-in period prior to the first dose of study drug. | Core Phase: Baseline to Weeks 9-12; Extension Period: Baseline to Week 24 | 
| Change From Baseline in Daily Number of Cutaneous Flushing Episodes | Participants recorded the number of daily cutaneous flushing episodes experienced in the daily diary. The change from baseline value was calculated as the difference between the mean numbers of cutaneous flushing episodes of the post-baseline interval (Weeks 9 to 12) and baseline. Baseline for the Extension Period was defined as non-missing assessment in Run-in period prior to the first dose of study drug. | Core Phase: Baseline to Weeks 9-12; Extension Period: Baseline to Week 24 | 
| Number of Participants Achieving Clinically Meaningful Symptom Reduction in the Core Phase | Clinically meaningful symptom reduction was defined as either: a) an average of < 4 bowel movements per day over 15 consecutive days, b) a 50% reduction from baseline in the number of bowel movements, c) a positive response to the question regarding adequate relief, or d) a 50% reduction from baseline in the number of daily flushing episodes. | Baseline to Week 12 | 
| Change From Baseline in Urinary 5-Hydroxyindoleacetic Acid (HIAA) Levels | Urinary 5-HIAA (u5-HIAA) is a standard test used in clinical practice to assess the neuroendocrine tumor (NET) activity and is collected as a 24-hour urine specimen. The change from baseline value for the Extension Period was calculated as the difference between mean change in 5-HIAA of the post-baseline interval (Weeks 20 to 21) and baseline. A negative change from baseline indicates improvement. Baseline for the Extension Period was defined as non-missing assessment in Run-in period prior to the first dose of study drug. | Core Phase: Baseline to Week 12; Extension Period: Baseline to Weeks 20-21 |