Telotristat With Lutathera in Neuroendocrine Tumors

Study Overview
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Brief Summary
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This trial will test the hypothesis that Telotristat treatment increases the antitumor efficacy of Lutetium Lu 177 Dotatate therapy in neuroendocrine tumors (NETs).

Detailed Description
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Neuroendocrine tumors (NETs) are a very heterogeneous group of tumors that develop predominantly in the gastrointestinal and pulmonary systems. Clinical detection and diagnosis are more reliable at late stages when metastatic spread has occurred. Patients with advanced disease may suffer from complications of uncontrolled hormone secretion and usually succumb due to tumor progression. This trial tests the hypothesis that inhibition of serotonin production with Telotristat will lead to cytostatic effects on neuroendocrine tumors and will complement the anti-tumor activity of Lutetium 177 Dotatate. The proposed combination may result in improved treatment efficacy as reflected by improved 20-month progression-free survival (PFS) as compared to historical control.

Official Title
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Study of Telotristat (Xermelo) in Combination With Luetetium Lu177 Dotatate (Lutathera) in Well-Differentiated Neuroendocrine Tumors

Conditions
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Neuroendocrine Tumors

Intervention / Treatment
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* Drug: Telotristat (Low-Dose)
* Drug: Telotristat (High-Dose)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Metastatic, or unresectable, histologically confirmed well-differentiated grade 1 and 2 neuroendocrine tumor with a positive gallium 68 Dotatate scan within 6 months prior to study enrollment Baseline CT scan or MRI with measurable progressive disease based on RECIST Criteria Failure of at least one prior systemic cancer treatment for this diagnosis Recovered from Adverse Events of previously administered therapeutic agents to Grade 2 or less toxicity according to CTCAE version 5.0 Eastern Cooperative Oncology Group (ECOG) performance status ≤2 normal organ and marrow function Exclusion Criteria: Prior exposure to Lutetium Lu 177 Dotatate History of allergic reactions attributed to compounds of similar chemical or biologic composition to Telotristat or Lutetium Lu 177 Dotatate. Presence of unstable angina or myocardial infarction New York Heart Association (NYHA) Class III or IV heart failure uncontrolled angina history of severe coronary artery disease, severe uncontrolled ventricular arrhythmias, sick sinus syndrome, or electrocardiographic evidence of acute ischemia or Grade 3 conduction system abnormalities Pregnant or lactating women Women of childbearing potential or male patients of reproductive potential Any other significant medical or psychiatric condition, currently uncontrolled by treatment, which may interfere with completion of the study

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 100 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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1: Low-Dose Telotristat<br>Participants in this group will receive 750mg Telotristat per day. | Drug: Telotristat (Low-Dose)<br>* Participants in this group will receive Lutetium Lu 177 Dotate (Lutathera) by IV every 2 months (Q8weeks) for a total of 4 doses. They will also receive oral Telotristat at 750mg per day (250mg TID) for 20 months.<br>* Other names: Xermelo;|
| Experimental: Arm 2: High-Dose Telotristat<br>Participants in this group will receive 1500mg Telotristat per day. | Drug: Telotristat (High-Dose)<br>* Participants in this group will receive Lutetium Lu 177 Dotate (Lutathera) by IV every 2 months (Q8weeks) for a total of 4 doses. They will also receive oral Telotristat at 1500mg per day (500mg TID) for 20 months.<br>* Other names: Xermelo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival (PFS) | Progression-free survival at 20 months. | 20 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR) | Overall response rate using RECIST v1.1 at 6 and 12 months after therapy | 6 and 12 months | 
| Median Progression-Free Survival (PFS) | Median progression-free survival. | 36 month | 
| Urinary 5-HIAA | Levels of urinary 5-Hydroxyindoleacetic acid (5-HIAA) will be measured at baseline and 12 months. | Baseline and 12 months | 
| Quality of Life (QLQ-C30) | The Quality of Life Questionnaire C30 (QLQ-C30) was developed by the European Organization for Research and Treatment of Cancer (EORTC) to assess quality of life in cancer patients.It includes five function domains (physical, emotional, social, role, cognitive), eight symptoms (fatigue, pain, nausea/vomiting, constipation, diarrhea, insomnia, dyspnea, and appetite loss), as well as global health/quality-of-life and financial impact. Subjects respond on a four-point scale from not at all to very much for most items.Raw scores are linearly converted to a 0-100 scale with higher scores reflecting higher levels of function and higher levels of symptom burden. | 20 month | 
| Quality of Life (QLQ-GI.NET21) | The Quality of Life GI Neuroendocrine Tumor survey (QLQ-GINET21) contains a total of 21 items: four single-item assessments relating to muscle and/or bone pain (MBP), body image (BI), information (INF) and sexual functioning (SX), together with 17 items organised into five proposed scales: endocrine symptoms (ED; three items), GI symptoms (GI; five items), treatment-related symptoms (TR; three items), social functioning (SF) and disease-related worries (DRW; three items). The response format of the questionnaire is a four-point Likert scale. Responses are linearly transformed to a 0-100 scale using EORTC guidelines, with higher scores reflecting more severe symptoms. | 20 month | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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NET