Study of Telotristat Etiprate (LX1606) in Participants With Symptomatic Carcinoid Syndrome Not Managed by Stable-Dose Octreotide Therapy

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the safety and tolerability of telotristat etiprate (LX1606) versus a placebo control in participants with symptomatic carcinoid syndrome not managed by stable-dose long-acting octreotide therapy. Following determination of the maximally tolerated or effective dose, cohort expansion will occur to confirm effect on symptoms and safety profile.

Official Title
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A Phase 2, Multicenter, Randomized, Double-blind, Placebo-controlled, Ascending, Multidose Study To Determine Safety and Tolerability of Orally Administered LX1606 in Subjects With Symptomatic Carcinoid Syndrome Refractory to Stable-Dose Octreotide Long-Acting Release Depot Therapy

Conditions
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Carcinoid Syndrome

Intervention / Treatment
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* Drug: Telotristat etiprate
* Drug: Octreotide LAR Depot
* Drug: Placebo


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 Symptoms not managed by stable-dose long-acting octreotide therapy (≥4 bowel movements per day) Ability to provide written informed consent Exclusion Criteria: ≥12 high volume, watery bowel movements per day associated with a clinical syndrome of volume contraction, dehydration, or hypotension compatible with a pancreatic cholera-type clinical syndrome 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 Previous exposure to a tryptophan hydroxylase (TPH) inhibitor 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: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Telotristat Etiprate 150 mg Core Phase<br>Telotristat etiprate capsules,150 mg orally 3 times daily for 28 days in the double-blind treatment period (core phase) in combination with stable-dose octreotide long-acting release (LAR) depot therapy given once per month. Upon completion of 28-days of treatment, participants were eligible to enter the optional open-label extension period. | Drug: Telotristat etiprate<br>* Telotristat etiprate capsules; orally 3 times daily.<br>* Other names: LX1606;Drug: Octreotide LAR Depot<br>* A stable-dose octreotide LAR depot therapy; administered subcutaneously once per month.<br>|
| Experimental: Telotristat Etiprate 250 mg Core Phase<br>Telotristat etiprate capsules, 250 mg orally 3 times daily for 28 days in the double-blind treatment period in combination with stable-dose octreotide LAR depot therapy given once per month. Upon completion of 28-days of treatment, participants were eligible to enter the optional open-label extension period. | Drug: Telotristat etiprate<br>* Telotristat etiprate capsules; orally 3 times daily.<br>* Other names: LX1606;Drug: Octreotide LAR Depot<br>* A stable-dose octreotide LAR depot therapy; administered subcutaneously once per month.<br>|
| Experimental: Telotristat Etiprate 350 mg Core Phase<br>Telotristat etiprate capsules, 350 mg orally 3 times daily for 28 days in the double-blind treatment period in combination with stable-dose octreotide LAR depot therapy given once per month. Upon completion of 28-days of treatment, participants were eligible to enter the optional open-label extension period. | Drug: Telotristat etiprate<br>* Telotristat etiprate capsules; orally 3 times daily.<br>* Other names: LX1606;Drug: Octreotide LAR Depot<br>* A stable-dose octreotide LAR depot therapy; administered subcutaneously once per month.<br>|
| Experimental: Telotristat Etiprate 500 mg Core Phase<br>Telotristat etiprate capsules, 500 mg orally 3 times daily for 28 days in the double-blind treatment period in combination with a stable-dose octreotide LAR depot therapy given once per month. Upon completion of 28-days of treatment, participants were eligible to enter the optional open-label extension period. | Drug: Telotristat etiprate<br>* Telotristat etiprate capsules; orally 3 times daily.<br>* Other names: LX1606;Drug: Octreotide LAR Depot<br>* A stable-dose octreotide LAR depot therapy; administered subcutaneously once per month.<br>|
| Experimental: Placebo Core Phase<br>Placebo-matching telotristat etiprate capsules, orally 3 times daily for 28 days in the double-blind treatment period in combination with stable-dose octreotide LAR depot therapy given once per month. Upon completion of 28-days of treatment, participants were eligible to receive telotristat etiprate in the optional open-label extension period. | Drug: Octreotide LAR Depot<br>* A stable-dose octreotide LAR depot therapy; administered subcutaneously once per month.<br>Drug: Placebo<br>* Placebo-matching telotristat etiprate capsules; orally 3 times daily.<br>|
| Experimental: Telotristat Etiprate Open-Label Extension Phase<br>Telotristat etiprate at assigned dose level for 8 weeks in combination with stable-dose octreotide LAR depot therapy given once per month in the open-label extension period. Upon completion of the 8-week period, participants could enter an additional extension period of 172 weeks, receiving telotristat etiprate at the assigned dose or maximum tolerated dose (500 mg 3 times daily). | Drug: Telotristat etiprate<br>* Telotristat etiprate capsules; orally 3 times daily.<br>* Other names: LX1606;Drug: Octreotide LAR Depot<br>* A stable-dose octreotide LAR depot therapy; administered subcutaneously once per month.<br>|

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 Event (TEAE) and Any Drug-related TEAE 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. A TEAE was an AE reported after the first dose of randomized treatment on Day 1. | Up to 4 Weeks Core Phase | 
| Number of Participants With Any TEAE in the Open-Label Extension Phase | An AE was defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related. A TEAE was an AE reported after receiving treatment. | Up to 180 weeks in the open-label extension phase | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Mean Number of Bowel Movements (BMs) Per Day | Participants recorded the number of BMs per day in a daily diary. The total number of BMs per day were averaged over the 4-week period. A negative change from Baseline indicates improvement. | Baseline to Week 4 | 
| Change From Baseline in Weekly Mean Stool Form | Participants recorded stool form in a daily diary using a 6-point scale (0-none,1-hard, 2-firm, 3-soft, 4-loose, 5-watery). A negative change from Baseline indicates improvement. | Baseline to Week 4 | 
| Change From Baseline in Percentage of Days Per Week Experiencing a Sensation of Urgency to Defecate | Participants recorded the sensation of urgency to defecate (Yes or No) in a daily diary. A negative change from Baseline indicates improvement. | Baseline to Week 4 | 
| Change From Baseline in Number of Cutaneous Flushing Episodes | Participants recorded the number of daily flushing episodes per day in a daily diary. The total number of flushing episodes per day were averaged over the 4-week period. A negative change from Baseline indicates improvement. | Baseline to Week 4 | 
| Change From Baseline in Severity of Abdominal Pain or Discomfort | Participants recorded the severity of abdominal pain or discomfort in a daily diary assessed using a 4-point scale (0-none, 1-mild, 2-moderate, 3-severe). A negative change from Baseline indicates improvement. | Baseline to Week 4 | 
| Change From Baseline in Urinary 5-hydroxyindoleacetic Acid (u5-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. A negative change from Baseline indicates improvement. | Baseline to Week 4 | 
| Change From Baseline in Chromogranin A | Blood samples were collected for assessment of Chromogranin A level. A negative change from Baseline indicates improvement. | Baseline to Week 4 | 
| Number of Participants Reporting Improvement in the Subjective Global Assessment of Symptoms Associated With Carcinoid Syndrome | Participants were asked to answer 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 number of participants who answered Yes are reported. | Week 4 | 
| Change From Baseline in Frequency of Rescue for Short-acting Octreotide Use/Day | Participants recorded details (location and frequency of injection) of subcutaneous injections of rescue, short-acting octreotide, if taken, in the daily diary. A negative change from Baseline indicates improvement. | Baseline to Week 4 | 
| Time to First Rescue, Short-acting Octreotide | Time to the first subcutaneous injections of rescue, short-acting octreotide was determined from the participant's daily diary. | Baseline to Week 4 | 
| Number of Participants Experiencing Complete Response at Week 4 | Complete Response to treatment was defined as one of the following: 1. Less than 4 bowel movements per day; or 2. A decrease in daily bowel movements that is ≥ 50% from baseline; or 3. A positive response to the global assessment 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?) for each of the last 2 weeks of the Treatment Period. | Baseline to Week 4 |