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

• ClinicalTrials.gov Identifier: NCT00853047
• Recruitment Status: Completed
• First Posted: February 27, 2009
• Results First Posted: December 26, 2018
• Last Update Posted: December 26, 2018
• Sponsor: Lexicon Pharmaceuticals
• Information provided by (Responsible Party): Lexicon Pharmaceuticals

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Carcinoid Syndrome	Drug: Telotristat etiprate; Drug: Octreotide LAR Depot; Drug: Placebo	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 23 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: 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
• Study Start Date: March 2009
• Actual Primary Completion Date: June 2014
• Actual Study Completion Date: June 2014

Arms and Interventions

Arm	Intervention/treatment
Experimental: Telotristat Etiprate 150 mg Core Phase; 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; Telotristat etiprate capsules; orally 3 times daily.; Other Name: LX1606; Drug: Octreotide LAR Depot; A stable-dose octreotide LAR depot therapy; administered subcutaneously once per month.
Experimental: Telotristat Etiprate 250 mg Core Phase; 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; Telotristat etiprate capsules; orally 3 times daily.; Other Name: LX1606; Drug: Octreotide LAR Depot; A stable-dose octreotide LAR depot therapy; administered subcutaneously once per month.
Experimental: Telotristat Etiprate 350 mg Core Phase; 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; Telotristat etiprate capsules; orally 3 times daily.; Other Name: LX1606; Drug: Octreotide LAR Depot; A stable-dose octreotide LAR depot therapy; administered subcutaneously once per month.
Experimental: Telotristat Etiprate 500 mg Core Phase; 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; Telotristat etiprate capsules; orally 3 times daily.; Other Name: LX1606; Drug: Octreotide LAR Depot; A stable-dose octreotide LAR depot therapy; administered subcutaneously once per month.
Experimental: Placebo Core Phase; 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; A stable-dose octreotide LAR depot therapy; administered subcutaneously once per month.; Drug: Placebo; Placebo-matching telotristat etiprate capsules; orally 3 times daily.
Experimental: Telotristat Etiprate Open-Label Extension Phase; 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; Telotristat etiprate capsules; orally 3 times daily.; Other Name: LX1606; Drug: Octreotide LAR Depot; A stable-dose octreotide LAR depot therapy; administered subcutaneously once per month.

Outcome Measures

Primary Outcome Measures :

1. Number of Participants With Any Treatment-emergent Adverse Event (TEAE) and Any Drug-related TEAE in the Core Phase [ Time Frame: Up to 4 Weeks 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.
2. Number of Participants With Any TEAE in the Open-Label Extension Phase [ Time Frame: Up to 180 weeks 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.

Secondary Outcome Measures :

1. Change From Baseline in Mean Number of Bowel Movements (BMs) Per Day [ Time Frame: Baseline to Week 4 ]
   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.
2. Change From Baseline in Weekly Mean Stool Form [ Time Frame: Baseline to Week 4 ]
   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.
3. Change From Baseline in Percentage of Days Per Week Experiencing a Sensation of Urgency to Defecate [ Time Frame: Baseline to Week 4 ]
   Participants recorded the sensation of urgency to defecate (Yes or No) in a daily diary. A negative change from Baseline indicates improvement.
4. Change From Baseline in Number of Cutaneous Flushing Episodes [ Time Frame: Baseline to Week 4 ]
   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.
5. Change From Baseline in Severity of Abdominal Pain or Discomfort [ Time Frame: Baseline to Week 4 ]
   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.
6. Change From Baseline in Urinary 5-hydroxyindoleacetic Acid (u5-HIAA) [ Time Frame: Baseline to Week 4 ]
   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.
7. Change From Baseline in Chromogranin A [ Time Frame: Baseline to Week 4 ]
   Blood samples were collected for assessment of Chromogranin A level. A negative change from Baseline indicates improvement.
8. Number of Participants Reporting Improvement in the Subjective Global Assessment of Symptoms Associated With Carcinoid Syndrome [ Time Frame: Week 4 ]
   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.
9. Change From Baseline in Frequency of Rescue for Short-acting Octreotide Use/Day [ Time Frame: Baseline to Week 4 ]
   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.
10. Time to First Rescue, Short-acting Octreotide [ Time Frame: Baseline to Week 4 ]
    Time to the first subcutaneous injections of rescue, short-acting octreotide was determined from the participant's daily diary.
11. Number of Participants Experiencing Complete Response at Week 4 [ Time Frame: Baseline to 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.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

Contacts and Locations

Locations

United States, Arkansas

Hematology Oncology Services of Arkansas

Little Rock, Arkansas, United States, 72205

United States, California

UCSF Helen Diller Family Comprehensive Cancer Center

San Francisco, California, United States, 94115

United States, Indiana

St. Francis Medical Group Oncology and Hematology Specialists

Indianapolis, Indiana, United States, 46237

United States, Iowa

University of Iowa

Iowa City, Iowa, United States, 52242

United States, Massachusetts

Dana Farber Cancer Institute

Boston, Massachusetts, United States, 02115

United States, Nebraska

Nebraska Methodist Hospital

Omaha, Nebraska, United States, 68114

United States, Texas

UT M.D. Anderson Cancer Center

Houston, Texas, United States, 77030

Texas Oncology - McAllen

McAllen, Texas, United States, 78503

Texas Oncology - Weslaco

Weslaco, Texas, United States, 78596

Sponsors and Collaborators

Lexicon Pharmaceuticals

Investigators

• Study Director: Pablo Lapuerta, MD; Lexicon Pharmaceuticals, Inc.

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Gelhorn HL, Kulke MH, O'Dorisio T, Yang QM, Jackson J, Jackson S, Boehm KA, Law L, Kostelec J, Auguste P, Lapuerta P. Patient-reported Symptom Experiences in Patients With Carcinoid Syndrome After Participation in a Study of Telotristat Etiprate: A Qualitative Interview Approach. Clin Ther. 2016 Apr;38(4):759-68. doi: 10.1016/j.clinthera.2016.03.002. Epub 2016 Mar 31.

Kulke MH, O'Dorisio T, Phan A, Bergsland E, Law L, Banks P, Freiman J, Frazier K, Jackson J, Yao JC, Kvols L, Lapuerta P, Zambrowicz B, Fleming D, Sands A. Telotristat etiprate, a novel serotonin synthesis inhibitor, in patients with carcinoid syndrome and diarrhea not adequately controlled by octreotide. Endocr Relat Cancer. 2014 Oct;21(5):705-14. doi: 10.1530/ERC-14-0173. Epub 2014 Jul 10.

• Responsible Party: Lexicon Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT00853047
• Other Study ID Numbers: LX1606.1-202-CS; LX1606.202 ( Other Identifier: Lexicon Pharmaceuticals, Inc. )
• First Posted: February 27, 2009
• Results First Posted: December 26, 2018
• Last Update Posted: December 26, 2018
• Last Verified: October 2018

Additional relevant MeSH terms:

Carcinoid Tumor; Malignant Carcinoid Syndrome; Syndrome; Serotonin Syndrome; Disease; Pathologic Processes; Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Drug-Related Side Effects and Adverse Reactions; Chemically-Induced Disorders; Octreotide; Gastrointestinal Agents; Antineoplastic Agents, Hormonal; Antineoplastic Agents