Telotristat Ethyl for the Treatment of Carcinoid Heart Disease in Patients With Metastatic Neuroendocrine Tumor

PRIMARY OBJECTIVE:

I. To estimate the percent change in N-terminal pro B-type natriuretic peptide (NT-proBNP) at 6 month visit from baseline after initiation of study drug in each arm and to compare the percent change between the two study arms.

SECONDARY OBJECTIVES:

I. To evaluate the change in functional capacity from baseline at 3 and 6 month visits as assessed by a 6 minute walk test (6MWT) in each arm.

II. To evaluate changes in echocardiographic parameters (Carcinoid Valvular Heart Disease \[CVHD\] score, global longitudinal myocardial strain assessment of the left and right ventricle/tricuspid annular plane systolic excursion \[TAPSE\]) from baseline to 3 and 6 month visits in each arm.

III. To evaluate the change from baseline to 3 and 6 month visits in plasma 5-hydroxyindoleacetic acid (5-HIAA) levels in each arm.

IV. To evaluate the change from baseline to 3 and 6 month visits in high sensitivity troponin T in each arm.

V. To evaluate the change from baseline to 3 and 6 month visits in health related quality of life with using the MD Anderson Symptom Inventory (MDASI) in each arm.

VI. To evaluate compliance of medications.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM A: Patients receive telotristat ethyl orally (PO) three times daily (TID) and somatostatin analog therapy (SSA) for 6 months in the absence of disease progression or unacceptable toxicity.

ARM B: Patients receive placebo PO TID and SSA for 6 months in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 30 days.

• Placebo Administration (Drug): Given PO
• Questionnaire Administration (Other): Ancillary studies
• Telotristat Ethyl (Drug): Given PO

Primary outcomes

• Percent Change in NTproBNP at 6 Months Visit From Baseline [Baseline and at 6 months]: Percent change in N-terminal pro B-type natriuretic peptide (NT-proBNP) from baseline to 6 months defined as (NTproBNP at 6 month - NTproBNP at baseline)/(NTproBNP at baseline)*100

Secondary outcomes

• Change in 6MWT at 3 Month Visit [Baseline and 3 month follow-up]: Change in functional capacity from baseline to 3-month visit, assessed by a 6-minute walk test (6MWT), where 6MWT is defined as the distance walked in 6 minutes, and the change is calculated as: 6MWT at 3 months minus 6MWT at baseline
• Change in 6MWT at 6 Month Visit [Baseline and 6 month follow-up]: Change in functional capacity from baseline to 6-month visit, assessed by a 6-minute walk test (6MWT), where 6MWT is defined as the distance walked in 6 minutes, and the change is calculated as: 6MWT at 6 months minus 6MWT at baseline
• Change in CVHD % Score From Baseline to 3 Month Visit [Baseline and 3 month follow-up]: The Carcinoid Valvular Heart disease (CVHD) % score at 3 months minus CVHD % score at baseline. CVHD score was determined by 1) tricuspid valve appearance, 2) tricuspid regurgitation severity by either spectral pulsed wave or color dopplet flow mapping, 3) pulmonary stenosis severity by spectral pulsed or continuous wave Doppler, and 4) pulmonary insufficiency severity by color Doppler. CVHD % score was calculated as total points assigned across four echo parameters (specified above 1-4)) divided by the maximum possible points (14) and multiplied by 100. The CVHD % score ranges from 0% to 100%, with higher values indicating more severe disease. The change in CVHD % score from baseline to 3 months reflects disease progression or improvement: a positive change indicates worsening valvular involvement, a negative change indicates improvement, and zero indicates stability.
• Change in CVHD Score From Baseline to 6 Month Visit [Baseline and 6 month follow-up]: The Carcinoid Valvular Heart disease (CVHD) % score at 6 months minus CVHD % score at baseline. CVHD score was determined by 1) tricuspid valve appearance, 2) tricuspid regurgitation severity by either spectral pulsed wave or color dopplet flow mapping, 3) pulmonary stenosis severity by spectral pulsed or continuous wave Doppler, and 4) pulmonary insufficiency severity by color Doppler. CVHD % score was calculated as total points assigned across four echo parameters divided by the maximum possible points (14) and multiplied by 100. The CVHD % score ranges from 0% to 100%, with higher values indicating more severe disease. The change in CVHD % score from baseline to 6 months reflects disease progression or improvement: a positive change indicates worsening valvular involvement, a negative change indicates improvement, and zero indicates stability.
• Percentage of Participants With Significant Change in Strain-RV From Baseline at 3 Months [Baseline and 3 month follow-up]: Percentage of participants with a significant change in right ventricular global longitudinal strain (strain-RV) from baseline to 3 months. A significant change is defined as an 15% or more change (increase or decrease) from baseline to 3 months. The Exact 2-sided 95% CI is based on the observed proportion of participants.
• Percentage of Participants With Significant Change in Strain-RV From Baseline at 6 Months [Baseline and 6 month follow-up]: Percentage of participants with a significant change in right ventricular global longitudinal strain (strain-RV) from baseline to 6 months. A significant change is defined as an 15% or more change (increase or decrease) from baseline to 6 months. The Exact 2-sided 95% CI is based on the observed proportion of participants.
• Percentage of Participants With Significant Change in Strain-LV From Baseline at 3 Months [Baseline and 3 month follow-up]: Percentage of participants with a significant change in left ventricular global longitudinal strain (strain-LV) from baseline to 3 months. A significant change is defined as an 15% or more change (increase or decrease) from baseline to 3 months. The Exact 2-sided 95% CI is based on the observed proportion of participants.
• Percentage of Participants With Significant Change in Strain-LV From Baseline at 6 Months [Baseline and 6 month follow-up]: Percentage of participants with a significant change in left ventricular global longitudinal strain (strain-LV) from baseline to 6 months. A significant change is defined as an 15% or more change (increase or decrease) from baseline to 6 months. The Exact 2-sided 95% CI is based on the observed proportion of participants.
• Percentage of Participants With Normal TAPSE at 3 Months [3 month follow-up]: Percentage of participants with a normal Tricuspid Annular Plane Systolic Excursion (TAPSE) at 3 months, where TAPSE ≥1.6cm is defined as normal. The Exact 2-sided 95% CI is based on the observed proportion of participants.
• Percentage of Participants With Normal TAPSE at 6 Months [6 month follow-up]: Percentage of participants with a normal Tricuspid Annular Plane Systolic Excursion (TAPSE) at 6 months, where TAPSE ≥1.6cm is defined as normal. The Exact 2-sided 95% CI is based on the observed proportion of participants.
• Change in 5HIAA From Baseline to 3 Months [Baseline and 3 month follow-up]: Change in plasma 5HIAA (5-Hydroxyindoleacetic acid) level from baseline to 3 months. The change is calculated as: 5HIAA at 3 months minus 5HIAA at baseline
• Change in 5HIAA From Baseline to 6 Months [Baseline and 6 month follow-up]: Change in 5HIAA measurement from baseline to 6 months
• Change in Troponin From Baseline to 3 Months [Baseline and 3 months follow-up]: Change in troponin level from baseline to 3 months, calculated as: troponine at 3 months minus troponin at baseline
• Change in Troponin From Baseline to 6 Months [Baseline and 6 months follow-up]: Change in troponin level from baseline to 6 months, calculated as: troponine at 6 months minus troponin at baseline
• Change in MDASI Mean Core Symptom Score From Baseline to 3 Months [Baseline and 3 months follow-up]: Change in MD Anderson Symptom Inventory (MDASI) mean core symptom score from baseline to 3 months. The MDASI mean core symptom score is calculated as the mean of 13 core symptom items, each ranged from 0 ( "not present") to 10 being ("as bad as you can imagine"), with the higher scores indicating worse symptoms. The change is computed as: score at 3 months minus score at baseline
• Change in Core Symptom Score From Baseline to 6 Months [Baseline and 6 months follow-up]: Change in MD Anderson Symptom Inventory (MDASI) mean core symptom score from baseline to 6 months. The MDASI mean core symptom score is calculated as the mean of 13 core symptom items, each ranged from 0 ( "not present") to 10 being ("as bad as you can imagine"), with the higher scores indicating worse symptoms. The change is computed as: score at 6 months minus score at baseline
• Change in MDASI Mean Total Symptom Score From Baseline to 3 Months [Baseline and 3 months follow-up]: Change in MD Anderson Symptom Inventory (MDASI) mean total symptom score from baseline to 3 months. The MDASI mean total symptom score is calculated as the mean symptom severity of 21 symptom items (13 core symptom items and 8 additional symptom items), each ranged from 0 ( "not present") to 10 being ("as bad as you can imagine), with the higher scores indicating worse symptoms. The change is computed as: score at 3 months minus score at baseline
• Change in MDASI Mean Total Symptom Score From Baseline to 6 Months [Baseline and 6 months follow-up]: Change in MD Anderson Symptom Inventory (MDASI) mean total symptom score from baseline to 6 months. The MDASI mean total symptom score is calculated as the mean symptom severity of 21 symptom items (13 core symptom items and 8 additional symptom items), each ranged from 0 ( "not present") to 10 being ("as bad as you can imagine), with the higher scores indicating worse symptoms. The change is computed as: score at 6 months minus score at baseline
• Change in MDASI Mean Interference Score From Baseline to 3 Months [Baseline and 3 months follow-up]: Change in MD Anderson Symptom Inventory (MDASI) mean interference score from baseline to 3 months. The MDASI mean interference score is calculated as the mean of 6 interference items, each ranged from 0 ( "not present") to 10 being ("as bad as you can imagine"), with the higher scores indicating worse interference. The change is computed as: score at 3 months minus score at baseline
• Change in Interference Score From Baseline to 6 Months [Baseline and 6 months follow-up]: Change in MD Anderson Symptom Inventory (MDASI) mean interference score from baseline to 6 months. The MDASI mean interference score is calculated as the mean of 6 interference items, each ranged from 0 ( "not present") to 10 being ("as bad as you can imagine"), with the higher scores indicating worse interference. The change is computed as: score at 6 months minus score at baseline
• Compliance>=70% While the Patients Were in the Study [Baseline, 3 months follow-up, 6 months follow-up]: Percentage of participants classified as compliant (compliance≥70%) during the study. Compliance is calculated as the total number of pills taken divided by the toal number of pills dispensed while the patient was on the study. Participants with compliance≥70% are considered compliant; otherwise, not compliant.

Sex: All, ages: 18 Years to any

Inclusion Criteria:

* Patients who are >= 18 years old will be eligible for the study
* Histopathologically-confirmed,metastatic neuroendocrine tumor and/or locally/regionally advanced neuroendocrine tumor
* Documented history of carcinoid syndrome based on clinical parameters
* Currently receiving stable-dose somatostatin analog (SSA) therapy defined as >= 2 months

  * Dose of long-acting release (LAR) or depot SSA therapy and on at least:

    * Octreotide LAR at 30 mg every 4 weeks
    * Lanreotide depot at 120 mg every 4 weeks
    * Patients who cannot tolerate SSA therapy at a level indicated above will be allowed to enter at their highest tolerated dose
* Ability and willingness to provide written informed consent
* Patients of childbearing potential must agree to use an adequate method of contraception during the study and for 30 days after the last dose of telotristat ethyl

  * Childbearing potential is defined as those who have not undergone surgical sterilization (eg. documented hysterectomy, tubal ligation, or bilateral salpingo-oophorectomy) or those who are not considered postmenopausal (defined as 12 months of spontaneous amenorrhea).
  * Adequate methods of contraception, defined as having a failure rate of < 1% per year, for patients or their partner include the following: condom with spermicidal gel, diaphragm with spermicidal gel, intrauterine device, surgical sterilization, vasectomy, oral contraceptive pill, depo-progesterone injections, progesterone implant (ie, Implanon), patch (Ortho Evra), NuvaRing, and abstinence. If a patient is not sexually active but becomes active, he or his partner should use medically accepted forms of contraception
* Eastern Cooperative Oncology Group (ECOG) 0-2

Exclusion Criteria:

* Previous exposure to telotristat ethyl (XERMELO) in the last 3 months
* History of active treatment for malignancy, other than neuroendocrine tumor (malignancies that in the opinion of the Investigator are considered cured, may participate)
* Treatment with any tumor directed therapy, including interferon, chemotherapy, mechanistic target of rapamycin (mTOR) inhibitors < 4 weeks prior to screening, or hepatic embolization, radiotherapy, peptide receptor radionuclide therapy, and/or tumor debulking < 12 weeks prior to screening
* History of short bowel syndrome or other known causes of diarrhea unrelated to carcinoid syndrome
* Clinically significant (as per primary investigators judgement) cardiac arrhythmia, bradycardia, tachycardia that would compromise patient safety or the outcome of the study
* Estimated glomerular filtration rate estimated glomerular filtration rate (eGFR) < 30 ml/min
* Hepatic laboratory values of aspartate transaminase (AST) or alanine aminotransferase (ALT):

  * > 5 x upper limit of normal (ULN) if patient has documented history of hepatic metastases; or
  * > 2.5 x ULN if no liver metastases are present
* Pregnant or lactating patients
* Patients receiving everolimus due to poor response to SSA
* Life expectancy < 6 months
* Any other clinically significant laboratory abnormality that would compromise patient safety or the outcome of the study as per primary investigators judgement
* Any clinically significant and/or uncontrolled cardiac-related abnormality that would compromise patient safety or the outcome of the study including as per primary investigators judgement, but not limited to:

  * Arrhythmia causing hemodynamic compromise
  * Symptomatic severe valvular disease
  * Symptomatic congestive heart failure classified by New York Heart Association (NYHA) class IV
  * Evidence of ischemia on electrocardiography (ECG) with chest pain
  * Unstable angina pectoris
* Current complaints of persistent constipation or history of chronic constipation, bowel obstruction or fecaloma within the past 6 months
* Investigator assessment of known history and/or uncontrolled hepatitis B surface antigen (HBsAg), hepatitis C antibody (HCV Ab), or human immunodeficiency virus (HIV)-1 or HIV-2
* History of substance or alcohol abuse (Diagnostic and Statistical Manual of Mental Disorders 5th edition \[DSM-V\] Criteria for Substance-Related Disorders) within the past 2 years
* History of galactose intolerance, deficiency of Lapp lactase, or glucose-galactose malabsorption
* Receipt of any investigational agent or study treatment (other treatment nor approved by Food and Drug Administration \[FDA\] for carcinoid syndrome or carcinoid heart disease) within the past 30 days
* Existence of any surgical or medical condition that, in the judgment of the Investigator, might compromise patient safety or the outcome of the study
* Presence of any clinically significant findings (relative to the patient population) during review of medical history or upon PE that, in the investigator's opinion, would compromise patient safety or the outcome of the study (e.g., psychiatric illness/social situations that would limit compliance with study requirements)
* Unable or unwilling to communicate or cooperate with the Investigator for any reason

Participant flow

Outcome results

• Percent Change in NTproBNP at 6 Months Visit From Baseline (Primary), Median, Percent change from baseline: Placebo + SSA -9.1 (-32.4 to 14.3); Xermelo + SSA 1.4 (-32.4 to 53.8)
• Change in 6MWT at 3 Month Visit (Secondary), Median, meters: Placebo + SSA 0 (-35 to 45); Xermelo + SSA 8 (-25 to 64)
• Change in 6MWT at 6 Month Visit (Secondary), Median, meters: Placebo + SSA -14 (-63 to 39); Xermelo + SSA 25.5 (-27 to 67)
• Change in CVHD % Score From Baseline to 3 Month Visit (Secondary), Median, Scores on a scale: Placebo + SSA 0 (-7 to 0); Xermelo + SSA 0 (0 to 0)
• Change in CVHD Score From Baseline to 6 Month Visit (Secondary), Median, Scores on a scale: Placebo + SSA 0 (0 to 0); Xermelo + SSA 0 (0 to 0)
• Percentage of Participants With Significant Change in Strain-RV From Baseline at 3 Months (Secondary), Number, Percentage of Participants: Placebo + SSA 33.3 (0.8 to 90.6); Xermelo + SSA 42.9 (9.9 to 81.6)
• Percentage of Participants With Significant Change in Strain-RV From Baseline at 6 Months (Secondary), Number, Percentage of Participants: Placebo + SSA 42.9 (9.9 to 81.6); Xermelo + SSA 40 (5.3 to 85.3)
• Percentage of Participants With Significant Change in Strain-LV From Baseline at 3 Months (Secondary), Number, Percentage of Participants: Placebo + SSA 14.3 (0.4 to 57.9); Xermelo + SSA 28.6 (3.7 to 71.0)
• Percentage of Participants With Significant Change in Strain-LV From Baseline at 6 Months (Secondary), Number, Percentage of Participants: Placebo + SSA 13.3 (1.7 to 40.5); Xermelo + SSA 12.5 (1.6 to 38.4)
• Percentage of Participants With Normal TAPSE at 3 Months (Secondary), Number, Percentage of Participants: Placebo + SSA 100 (47.8 to 100); Xermelo + SSA 86 (42.1 to 99.6)
• Percentage of Participants With Normal TAPSE at 6 Months (Secondary), Number, Percentage of Participants: Placebo + SSA 100 (83.9 to 100); Xermelo + SSA 95 (75.1 to 99.9)
• Change in 5HIAA From Baseline to 3 Months (Secondary), Median, ng/mL: Placebo + SSA -0.9 (-4.2 to 6.6); Xermelo + SSA -55.3 (-118.2 to -28.6)
• Change in 5HIAA From Baseline to 6 Months (Secondary), Median, ng/mL: Placebo + SSA 0.1 (-1.9 to 7.3); Xermelo + SSA -56.4 (-104.4 to -18.6)
• Change in Troponin From Baseline to 3 Months (Secondary), Median, ng/L: Placebo + SSA 0 (-1 to 2); Xermelo + SSA 0 (-2 to 1)
• Change in Troponin From Baseline to 6 Months (Secondary), Median, ng/L: Placebo + SSA 0 (-1 to 1); Xermelo + SSA 0 (-2 to 1)
• Change in MDASI Mean Core Symptom Score From Baseline to 3 Months (Secondary), Median, Scores on a scale: Placebo + SSA -0.2 (-0.4 to 0.4); Xermelo + SSA 0.1 (-0.2 to 0.3)
• Change in Core Symptom Score From Baseline to 6 Months (Secondary), Median, Scores on a scale: Placebo + SSA 0 (-0.3 to 0.4); Xermelo + SSA 0 (-0.3 to 0.2)
• Change in MDASI Mean Total Symptom Score From Baseline to 3 Months (Secondary), Median, points: Placebo + SSA 0 (-0.3 to 0.5); Xermelo + SSA 0 (-0.2 to 0.2)
• Change in MDASI Mean Total Symptom Score From Baseline to 6 Months (Secondary), Median, Scores on a scale: Placebo + SSA -0.1 (-0.2 to 0.2); Xermelo + SSA 0 (-0.4 to 0.3)
• Change in MDASI Mean Interference Score From Baseline to 3 Months (Secondary), Median, Scores on a scale: Placebo + SSA 0 (-0.3 to 0.8); Xermelo + SSA 0 (-0.4 to 0.1)
• 2 more outcome measures not shown.

Adverse events

Time frame: Adverse events were monitored from baseline throughout the follow-up period (3-month and 6-month follow-up visits) and for up to 30 days after the last dose of the study drug, with the treatment period planned for 6-months

Serious adverse events by term

Other adverse events by term

• Study Protocol and Statistical Analysis Plan (PDF, 2025-12-11)

• Cezar A Iliescu, MD, Principal investigator, M.D. Anderson Cancer Center