Small Intestinal NETPhase 3TELEFIRSTNCT04065165
Lanreotide Combined With Telotristat Ethyl or Placebo for the First-line Treatment in Patients With Advanced Well Differentiated Small Intestinal Neuroendocrine Tumours (siNET) With Highly-functioning Carcinoid Syndrome
A Phase 3 study testing Telotristat Ethyl and Lanreotide in people with Small Intestinal NET and Carcinoid Heart Disease, run by European Organisation for Research and Treatment of Cancer - EORTC.
Trial summary
This is a randomized phase III clinical trial of Lanreotide combined with Telotristat ethyl or placebo for the first-line treatment in patients with advanced well differentiated small intestinal neuroendocrine tumours (siNET) with highly-functioning carcinoid syndrome to test whether telotristat ethyl plus lanreotide… Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Small Intestinal NET, Carcinoid Heart Disease
- What is being tested?
- Telotristat Ethyl and Lanreotide
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 0 participants
- Where
- No sites listed yet
- Study dates
- Apr 2020to Oct 2027
- Phase
- Phase 3
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Histologically confirmed well-differentiated (grade 1 or grade 2) neuroendocrine tumour from small bowel primary (or unknown primary suspected to be of small bowel origin) as per WHO / ENETS classification
- Advanced disease (locally advanced, metastatic or recurrent, according to TNM staging version 8 or ENETS latest classification), not amenable for curative surgery
- No previous systemic treatment for the advanced neuroendocrine tumour (including somatostatin analogue)
- Highly functioning carcinoid syndrome, defined as:
- Mean ≥4 bowel movements per day; patients will have a one-week run-in screening period for recording of frequency and consistency of diarrhea (Only those who complete the one-week run-in screening period and are ≥6 days out of 7 compliant with diary entries will be considered eligible and randomized).
- And
Show all 20Show fewer
- Serum, plasma or urine 5-HIAA levels ≥2 ULN (within 28 days of study entry)
- Age ≥18 years (no upper limit) and life expectancy >3 months
- Adequate haematological, hepatic and renal laboratory values:
- Neutrophils >1500 cells/mm3
- Platelets >75,000 cells/mm3
- Hemoglobin (Hgb) >9 g/dL for males and >8 g/dL for females
- Aspartate transaminase (AST) and alanine aminotransferase (ALT): <2.5 x upper limit of normal (ULN) if patient does not have documented history of hepatic metastases or <5.5 x ULN if patient has documented history of hepatic metastases
- Total bilirubin ≤1.5 x ULN (unless patient has a documented history of Gilbert's Syndrome)
- Alkaline phosphatase (ALP) <5 x ULN, if total bilirubin is >ULN
- Serum creatinine <1.5 x ULN and with creatinine clearance > 30 ml/min as calculated with MDRD Formula
- Women of child bearing potential (WOCBP) MUST have a negative serum pregnancy test within 3 days prior to the first dose of study treatment.
- Unless child bearing potential has been terminated by surgery / radical radiotherapy, women of childbearing / reproductive potential should use highly effective birth control measures, during the study treatment period and for at least 30 days after the last study treatment and then according to the investigator recommendation or national/institutional guideline. A highly effective method of birth control is defined as those which result in low failure rate (i.e. less than 1% per year) when used consistently and correctly.
- Female subjects who are breast feeding should discontinue nursing prior to the first dose of study treatment and until 5 months months after the last study treatment.
- Before patient registration/randomization, written informed consent must be given according to ICH/GCP, and national/local regulations.
Who cannot join
- Patients who are planned to be treated with other anti-tumour treatment (e.g. chemotherapy, liver embolization, Peptide Receptor Radionuclide Therapy (PRRT)) at the time of the study entry.
- Major surgery defined as procedures requiring general anesthesia or major regional anesthesia within 8 weeks prior to registration.
- Administration of any investigational therapeutic agent prior to registration (investigational imaging tracers are allowed).
- Patients who received any previous systemic treatment for carcinoid syndrome or tumour control (including SSA); previous use of anti-diarrheal medication such as loperamide or codeine is allowed.
- Patient with diarrhea and/or flushing due to any cause other than the neuroendocrine tumour such as fat malabsorption, bile acid malabsorption, enteric pathogens (parasites or clostridium difficile), short bowel syndrome (SBS) or malignancy.
- Allergy / history of hypersensitivity reaction to any of the treatment components.
Show all 19Show fewer
- Any evidence of severe or uncontrolled systemic disease which, in the view of the investigator, makes it undesirable for the patient to participate in the trial.
- Patients with end-stage renal disease requiring dialysis.
- Patients with severe hepatic impairment (Child-Pugh score C).
- Patients with known rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption.
- Any patient with a medical or psychiatric condition that impairs their ability to give informed consent.
- Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial.
- Inclusion/Exclusion Criteria for long-term follow-up for carcinoid heart disease (assessed locally)
- Patients diagnosed with carcinoid heart disease during the baseline or 12-month treatment period will be eligible
- Patients with suspected carcinoid heart disease but with poor/limited transthoracic echocardiogram windows, will not be eligible for long-term carcinoid heart disease follow-up
- Patients with moderate/severe valvular heart disease secondary to any pathology other than carcinoid heart disease (as classified by the ESC valvular heart disease guidelines10) are not eligible
- Patients with any pre-existing right sided heart disease such as arrythmogenic ventricular cardiomyopathy and patients with pre-existing atrial or ventricular arrythmia are not eligible
- Patients with pre-existing cardiomyopathy (such as hypertrophic cardiomyopathy or dilated cardiomyopathy) are not eligible
- Patients with implanted cardiac devices (i.e. pacemakers or an implantable cardioverter defibrillator) are not eligible
About this study
Official title: Randomized Phase III Clinical Trial of Lanreotide Combined With Telotristat Ethyl or Placebo for the First-line Treatment in Patients With Advanced Well Differentiated Small Intestinal Neuroendocrine Tumours (siNET) With Highly-functioning Carcinoid Syndrome
This is a randomized phase III clinical trial of Lanreotide combined with Telotristat ethyl or placebo for the first-line treatment in patients with advanced well differentiated small intestinal neuroendocrine tumours (siNET) with highly-functioning carcinoid syndrome to test whether telotristat ethyl plus lanreotide is more effective than placebo plus lanreotide in reducing the number of daily bowel movements.
In addition, the study allows evaluation of the biochemical response (5-HIAA and chromogranin-A), the reduction in the number of daily cutaneous flushing episodes, the improvement in abdominal pain/discomfort, health-related quality of life, improvement in gastro-intestinal and endocrine symptoms, changes in emotional functioning, the impact of discontinuation of telotristat ethyl/placebo on HRQOL and symptoms, and the safety and toxicity of the treatment.
Read more
Patients will enter into a screening/run-in period of 1 week to establish baseline characteristics and symptomatology. The baseline assessment of daily bowel movement, as assessed in an electronic diary, will be averaged over the run-in period.
Following the screening/run-in period, patients will be randomly assigned (1:1) to either the control arm or the experimental arm for 12 months. Randomization will be stratified according to the grade of tumour differentiation (grade 1 vs. grade 2) and by baseline number of bowel movements per day (4-6 versus >6). A total of 94 patients will be randomly assigned (1:1) to either arm.
Upon randomization, all patients will enter the 12-month treatment period with lanreotide + telotristat ethyl/placebo (blinded). In the experimental arm, patients will receive the deep subcutaneous injection of lanreotide (120 mg) every 28 days and 250 mg orally three times daily (TID) of telotristat ethyl for 12 months. In the control arm, patients will receive the deep subcutaneous injection of lanreotide every 28 days (120 mg) and placebo orally TID for 12 months.
After completion of a minimum of 6 months on randomized blinded-treatment, the protocol allows for patients on treatment with telotristat ethyl/placebo to be unblinded in the event of "lack of symptom control". Unblinding due to "lack of symptom control" can happen at any time between 6 and 12 months of the blinded-treatment period. After unblinding, patient will interrupt protocol treatment and will be further treated as per clinician discretion.
All patients will be unblinded after a maximum of 12 months on randomized blinded-treatment.
After a follow-up of 12 months, patients will go off study except patients with carcinoid heart disease. Patients off study will be further treated as per clinician discretion.
Patients with carcinoid heart disease will continue open-label treatment on study (lanreotide + telotristat ethyl or lanreotide alone according to what they were receiving at unblinding at 12 months) for 4 additional years (open-label extension period). Patients with carcinoid heart disease who discontinue protocol treatment before 12 months will also enter the extension period for additional follow-up. Additional follow-up will last 4 years for these patients and will include 6-monthly cardiological assessments.
All efficacy analyses will be conducted in the Intention-to-treat population as primary analyses i.e. all 94 randomized patients will be analyzed in the arm they were allocated by randomization. Safety analyses will be performed on the Safety population i.e. on all patients who have received at least one dose of the study drugs.
The translational research projects include blood metabolite discovery and targeted assays to find new biomarker candidates of response to Telotristat.
Human biological material that will be collected for translational research purpose:
- whole blood, plasma and serum at baseline, 4 hours after first dose, 4 weeks, 12 weeks and at end of treatment visit with telotristat/placebo (due to end of study, disease progression or lack of benefit)
- archival tissue samples (formalin-fixed paraffin-embedded) will be retrieved for all patients at study entry. In addition, one EDTA blood tube of whole blood (10 ml) at baseline, 12 weeks and end of treatment (EOT visit) might be also collected for not yet pre-defined and further translational research.
Quality of life will be assessed with the EORTC Quality of Life Questionnaire (QLQ-C30) version 3, together with the QLQ-GI.NET21 specific module designed for Neuroendocrine Tumours. The computer-adaptive testing (CAT) diarrhea scale will also be used. The baseline questionnaires must be completed during the screening period and before randomization. Subsequent questionnaires are completed at 4 weeks, 12 weeks, 24 weeks, 36 weeks and 52 weeks. Once a patient has stopped treatment, HRQoL data collection for that patient is required 1 month (28-35 days) after protocol treatment discontinuation.
- Conditions
- Small Intestinal NET, Carcinoid Heart Disease
- Being tested
- Telotristat Ethyl, Lanreotide
- Keywords
- intestinal NET, carcinoid syndrome, somatostatin analogues, tryptophan hydroxylase inhibitor
- Medical subject headings
- Carcinoid Heart Disease, Serotonin Syndrome
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Telotristat EthylDrug
Also called Xermelo
250 mg TID orally
LanreotideDrug
Also called Somatuline
120 mg Q4W deep subcutaneous injection in the superior external quadrant of the buttock or in the upper outer thigh
| Study group | Role | What they receive |
|---|---|---|
| Experimental arm | Experimental | Lanreotide 120 mg q4w Telotristat Ethyl 250 mg TID Receives: Drug: Telotristat Ethyl; Drug: Lanreotide |
| Control arm | Placebo comparator | Lanreotide 120 mg q4w Placebo TID Receives: Drug: Lanreotide |
What is being measured
The primary outcome is the main question the study is designed to answer.
Number of bowel movements (BMs)
The change from baseline in the number of bowel movements (BMs) per day
Measured: 43 months after first patient in
Secondary outcomes (3)
Urine/serum/plasma 5-HIAA and chromogranin-A
Intrapatient change from baseline in urine/serum/plasma 5-HIAA and chromogranin-A
Measured: 43 months after first patient in
Number of daily cutaneous flushing episodes
Change from baseline in the number of daily cutaneous flushing episodes.
Measured: 43 months after first patient in
Health Related Quality of Life (HRQoL)
Quality of life will be assessed with the EORTC Quality of Life Questionnaire (QLQ-C30) version 3. Scale measures are: not at all; a little; quite a bit; very much.
Measured: 43 months after first patient in
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted22 Aug 2019
- Study startApr 2020 (estimated)
- Primary completionJul 2023 (estimated)
- Study completionOct 2027 (estimated)
Why it stopped: Company decision
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Small Intestinal NETStudies of the same condition, open and under way.
- More trials run by European Organisation for Research and Treatment of Cancer - EORTCThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 0 participants (actual)
Sponsor and investigators
- Sponsor type
- Research network
- Collaborators
- Ipsen
- Responsible party
- Sponsor
- Investigators
- Juan Valle, Principal investigator, The Christie NHS Foundation Trust, Manchester, UKAngela Lamarca, Principal investigator, The Christie NHS Foundation Trust, Manchester, UK
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04065165
- Sponsor's protocol ID
- EORTC-1715-GITCG
- Acronym
- TELEFIRST
- Status last verified
- Jan 2020
- First submitted
- 14 Aug 2019
- Last updated
- 5 Feb 2020
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
Study at a glance
From the registry record, last updated by the sponsor on 5 Feb 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Randomized Phase III Clinical Trial of Lanreotide Combined With Telotristat Ethyl or Placebo for the First-line Treatment in Patients With Advanced Well Differentiated Small Intestinal Neuroendocrine Tumours (siNET) With Highly-functioning Carcinoid Syndrome
- ClinicalTrials.gov ID
- NCT04065165
- Acronym / sponsor ID
- TELEFIRST / EORTC-1715-GITCG
- Conditions
- Small Intestinal NET, Carcinoid Heart Disease
- Keywords
- intestinal NET, carcinoid syndrome, somatostatin analogues, tryptophan hydroxylase inhibitor
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- WithdrawnReason stopped: Company decision
- Enrolment
- 0 participants (actual)
- Lead sponsor
- European Organisation for Research and Treatment of Cancer - EORTCResearch network
- Collaborators
- Ipsen
- Study start
- Apr 2020 (estimated)
- Primary completion
- Jul 2023 (estimated)
- Study completion
- Oct 2027 (estimated)
- First posted
- 22 Aug 2019 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
This is a randomized phase III clinical trial of Lanreotide combined with Telotristat ethyl or placebo for the first-line treatment in patients with advanced well differentiated small intestinal neuroendocrine tumours (siNET) with highly-functioning carcinoid syndrome to test whether telotristat ethyl plus lanreotide is more effective than placebo plus lanreotide in reducing the number of daily bowel movements.
In addition, the study allows evaluation of the biochemical response (5-HIAA and chromogranin-A), the reduction in the number of daily cutaneous flushing episodes, the improvement in abdominal pain/discomfort, health-related quality of life, improvement in gastro-intestinal and endocrine symptoms, changes in emotional functioning, the impact of discontinuation of telotristat ethyl/placebo on HRQOL and symptoms, and the safety and toxicity of the treatment.
Patients will enter into a screening/run-in period of 1 week to establish baseline characteristics and symptomatology. The baseline assessment of daily bowel movement, as assessed in an electronic diary, will be averaged over the run-in period.
Following the screening/run-in period, patients will be randomly assigned (1:1) to either the control arm or the experimental arm for 12 months. Randomization will be stratified according to the grade of tumour differentiation (grade 1 vs. grade 2) and by baseline number of bowel movements per day (4-6 versus >6). A total of 94 patients will be randomly assigned (1:1) to either arm.
Upon randomization, all patients will enter the 12-month treatment period with lanreotide + telotristat ethyl/placebo (blinded). In the experimental arm, patients will receive the deep subcutaneous injection of lanreotide (120 mg) every 28 days and 250 mg orally three times daily (TID) of telotristat ethyl for 12 months. In the control arm, patients will receive the deep subcutaneous injection of lanreotide every 28 days (120 mg) and placebo orally TID for 12 months.
After completion of a minimum of 6 months on randomized blinded-treatment, the protocol allows for patients on treatment with telotristat ethyl/placebo to be unblinded in the event of "lack of symptom control". Unblinding due to "lack of symptom control" can happen at any time between 6 and 12 months of the blinded-treatment period. After unblinding, patient will interrupt protocol treatment and will be further treated as per clinician discretion.
All patients will be unblinded after a maximum of 12 months on randomized blinded-treatment.
After a follow-up of 12 months, patients will go off study except patients with carcinoid heart disease. Patients off study will be further treated as per clinician discretion.
Patients with carcinoid heart disease will continue open-label treatment on study (lanreotide + telotristat ethyl or lanreotide alone according to what they were receiving at unblinding at 12 months) for 4 additional years (open-label extension period). Patients with carcinoid heart disease who discontinue protocol treatment before 12 months will also enter the extension period for additional follow-up. Additional follow-up will last 4 years for these patients and will include 6-monthly cardiological assessments.
All efficacy analyses will be conducted in the Intention-to-treat population as primary analyses i.e. all 94 randomized patients will be analyzed in the arm they were allocated by randomization. Safety analyses will be performed on the Safety population i.e. on all patients who have received at least one dose of the study drugs.
The translational research projects include blood metabolite discovery and targeted assays to find new biomarker candidates of response to Telotristat.
Human biological material that will be collected for translational research purpose:
- whole blood, plasma and serum at baseline, 4 hours after first dose, 4 weeks, 12 weeks and at end of treatment visit with telotristat/placebo (due to end of study, disease progression or lack of benefit)
- archival tissue samples (formalin-fixed paraffin-embedded) will be retrieved for all patients at study entry. In addition, one EDTA blood tube of whole blood (10 ml) at baseline, 12 weeks and end of treatment (EOT visit) might be also collected for not yet pre-defined and further translational research.
Quality of life will be assessed with the EORTC Quality of Life Questionnaire (QLQ-C30) version 3, together with the QLQ-GI.NET21 specific module designed for Neuroendocrine Tumours. The computer-adaptive testing (CAT) diarrhea scale will also be used. The baseline questionnaires must be completed during the screening period and before randomization. Subsequent questionnaires are completed at 4 weeks, 12 weeks, 24 weeks, 36 weeks and 52 weeks. Once a patient has stopped treatment, HRQoL data collection for that patient is required 1 month (28-35 days) after protocol treatment discontinuation.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Experimental arm | Experimental | Drug: Telotristat Ethyl, Drug: LanreotideLanreotide 120 mg q4w Telotristat Ethyl 250 mg TID |
| Control arm | Placebo comparator | Drug: LanreotideLanreotide 120 mg q4w Placebo TID |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (20 listed)
- Histologically confirmed well-differentiated (grade 1 or grade 2) neuroendocrine tumour from small bowel primary (or unknown primary suspected to be of small bowel origin) as per WHO / ENETS classification
- Advanced disease (locally advanced, metastatic or recurrent, according to TNM staging version 8 or ENETS latest classification), not amenable for curative surgery
- No previous systemic treatment for the advanced neuroendocrine tumour (including somatostatin analogue)
- Highly functioning carcinoid syndrome, defined as:
- And
Key exclusion criteria (19 listed)
- Patients who are planned to be treated with other anti-tumour treatment (e.g. chemotherapy, liver embolization, Peptide Receptor Radionuclide Therapy (PRRT)) at the time of the study entry.
- Major surgery defined as procedures requiring general anesthesia or major regional anesthesia within 8 weeks prior to registration.
- Administration of any investigational therapeutic agent prior to registration (investigational imaging tracers are allowed).
- Patients who received any previous systemic treatment for carcinoid syndrome or tumour control (including SSA); previous use of anti-diarrheal medication such as loperamide or codeine is allowed.
- Patient with diarrhea and/or flushing due to any cause other than the neuroendocrine tumour such as fat malabsorption, bile acid malabsorption, enteric pathogens (parasites or clostridium difficile), short bowel syndrome (SBS) or malignancy.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Telotristat EthylAlso: Xermelo250 mg TID orally | Drug | Experimental arm |
| LanreotideAlso: Somatuline120 mg Q4W deep subcutaneous injection in the superior external quadrant of the buttock or in the upper outer thigh | Drug | Control arm, Experimental arm |
Primary outcome
Number of bowel movements (BMs)
Time frame: 43 months after first patient in
The change from baseline in the number of bowel movements (BMs) per day
3 secondary outcomes
Urine/serum/plasma 5-HIAA and chromogranin-A
Time frame: 43 months after first patient in
Number of daily cutaneous flushing episodes
Time frame: 43 months after first patient in
Health Related Quality of Life (HRQoL)
Time frame: 43 months after first patient in
Results and safety
The study was withdrawn before enrolling participants, so there are no results.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 5 Feb 2020.
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Juan Valle principal investigator
The Christie NHS Foundation Trust, Manchester, UK
Angela Lamarca principal investigator
The Christie NHS Foundation Trust, Manchester, UK
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Telotristat Ethyl and Lanreotide in people with Small Intestinal NET and Carcinoid Heart Disease, run by European Organisation for Research and Treatment of Cancer - EORTC.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 20 inclusion and 19 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: withdrawn, as of the sponsor's last update on 5 Feb 2020. Status can change between updates, so confirm with the study contact before making plans.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study was withdrawn before enrolling participants, so there are no results.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Number of bowel movements (BMs) (time frame: 43 months after first patient in). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 5 Feb 2020.