Clinical trial NCT04810091: Telotristat Ethyl for the Treatment of Carcinoid Heart Disease in Patients With Metastatic Neuroendocrine Tumor
Official title: TELEHEART: Telotristat Ethyl in a Heart Biomarker Study
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Locally Advanced Neuroendocrine Neoplasm
Metastatic Neuroendocrine Neoplasm
Lead sponsor: M.D. Anderson Cancer Center
Sponsor class: OTHER
First posted: 2021-03-22
Enrollment: 79
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This phase III trial compares the effect of telotristat ethyl and the current standard of care somatostatin analog therapy or somatostatin analog therapy alone in treating patients with neuroendocrine tumor that has spread to other places in the body (metastatic). Telotristat ethyl and somatostatin analog therapy may help to control carcinoid syndrome and carcinoid heart disease.

Detailed description: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Percent change in N-terminal pro B-type natriuretic peptide (NT-proBNP)
timeFrame: Baseline to 6 months
Secondary outcomes:
measure: Change in 6-minute walk test (6MWT)
timeFrame: Baseline to 3 and 6 months
measure: Change in Carcinoid Valvular Heart Disease (CVHD) score
timeFrame: Baseline to 3 and 6 months
measure: Change (significant change or non-significant change) in global longitudinal myocardial strain assessment of the left and right ventricle
timeFrame: Baseline to 3 and 6 months
measure: Change in tricuspid annular plane systolic excursion (normal vs. abnormal)
timeFrame: Baseline to 3 and 6 months
measure: Change in plasma 5-HIAA levels
timeFrame: Baseline to 3 and 6 months
measure: Change in high sensitivity troponin T
timeFrame: Baseline to 3 and 6 months
measure: Change in quality of life questionnaire
timeFrame: Baseline to 3 and 6 months
measure: Incidence of adverse events
timeFrame: Up to 6 months
Other outcomes:
Locations:
city: Houston
country: United States
facility: M D Anderson Cancer Center
state: Texas
Study officials:
affiliation: M.D. Anderson Cancer Center
name: Cezar A Iliescu, MD
role: PRINCIPAL_INVESTIGATOR
References: