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A Study Comparing Treatment With 177Lu-DOTA0-Tyr3-Octreotate to Octreotide LAR in Patients With Inoperable, Progressive, Somatostatin Receptor Positive Midgut Carcinoid Tumours (NETTER-1)

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ClinicalTrials.gov Identifier: NCT01578239
Recruitment Status : Completed
First Posted : April 16, 2012
Results First Posted : October 2, 2017
Last Update Posted : March 24, 2021
Sponsor:
Information provided by (Responsible Party):
Advanced Accelerator Applications

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Conditions Carcinoid Tumor of the Small Bowel
Neuroendocrine Tumour
Interventions Drug: Octreotide LAR
Drug: 177Lu-DOTA0-Tyr3-Octreotate
Enrollment 231
Recruitment Details Overall Study Table includes all subjects who were enrolled prior to the primary endpoint data cutoff when 74 events of progression free survival were reached (24 July 2015).
Pre-assignment Details  
Arm/Group Title 177Lu-DOTA0-Tyr3-Octreotate Octreotide LAR
Hide Arm/Group Description Cumulative dose of 29.6 GBq (800 mCi) 177Lu-DOTA0-Tyr3-Octreotate delivered over 4 doses Dosing regimen: - 4 doses of 7.4 GBq (200 mCi) 177Lu-DOTA0-Tyr3-Octreotate administered in 8±1-week intervals. Intervals could be extended up to 16 weeks to accommodate resolving acute toxicity (see Dose Modifying Toxicity (DMT) below) - amino acids will be given with each administration for kidney protection; Patients experiencing clinical symptoms (i.e. diarrhoea and flushing) associated with their carcinoid tumours, were given 30 mg Octreotide LAR s.c. rescue injections for symptom control purpose, unless the patient progresses or dies. 60 mg Octreotide LAR treatment every 4 weeks (i.m. injections) until the end of the study, unless the patient progresses or dies (see Dose Modifying Toxicity (DMT)); In case patients experience clinical symptoms (i.e. diarrhoea and flushing) associated with their carcinoid tumours, s.c. Octreotide rescue injections are allowed.
Period Title: Overall Study
Started [1] 116 113
Safety Set (SAF) [2] 112 111
Completed 94 88
Not Completed 22 25
[1]
All randomized patients at the efficacy cut-off date were included in Full Analysis dataset (FAS)
[2]
All patients who received/took trial medication who were randomized up to the safety cut-off date of 30 June 2016 were included in the Safety Set (SAF)
Arm/Group Title 177Lu-DOTA0-Tyr3-Octreotate Octreotide LAR Total
Hide Arm/Group Description Cumulative dose of 29.6 GBq (800 mCi) 177Lu-DOTA0-Tyr3-Octreotate delivered over 4 doses Dosing regimen: - 4 doses of 7.4 GBq (200 mCi) 177Lu-DOTA0-Tyr3-Octreotate administered in 8±1-week intervals. Intervals could be extended up to 16 weeks to accommodate resolving acute toxicity (see Dose Modifying Toxicity (DMT) below) - amino acids will be given with each administration for kidney protection; Patients experiencing clinical symptoms (i.e. diarrhoea and flushing) associated with their carcinoid tumours, were given 30 mg Octreotide LAR s.c. rescue injections for symptom control purpose, unless the patient progresses or dies. 60 mg Octreotide LAR treatment every 4 weeks (i.m. injections) until the end of the study, unless the patient progresses or dies (see Dose Modifying Toxicity (DMT)); In case patients experience clinical symptoms (i.e. diarrhoea and flushing) associated with their carcinoid tumours, s.c. Octreotide rescue injections are allowed. Total of all reporting groups
Overall Number of Baseline Participants 116 113 229
Hide Baseline Analysis Population Description
All patients who were randomized in the study.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 116 participants 113 participants 229 participants
63.3  (9.4) 64.1  (9.7) 63.7  (9.53)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 116 participants 113 participants 229 participants
Female
53
  45.7%
60
  53.1%
113
  49.3%
Male
63
  54.3%
53
  46.9%
116
  50.7%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 116 participants 113 participants 229 participants
Belgium 4 2 6
France 12 9 21
Germany 10 7 17
Italy 5 9 14
Portugal 1 0 1
Spain 5 6 11
United Kingdom 13 11 24
United States 66 69 135
1.Primary Outcome
Title Progression Free Survival (PFS)
Hide Description Progression is defined using Response Evaluation Criteria in Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. CT/MRI tumour assessment in both arms are performed every 12±1 weeks from the first treatment date.
Time Frame after 74 centrally confirmed cases disease progression or death
Hide Outcome Measure Data
Hide Analysis Population Description
Full analysis data set
Arm/Group Title 177Lu-DOTA0-Tyr3-Octreotate Octreotide LAR
Hide Arm/Group Description:
[Not Specified]
[Not Specified]
Overall Number of Participants Analyzed 116 113
Median (95% Confidence Interval)
Unit of Measure: months
NA [1] 
(NA to NA)
8.5
(5.8 to 9.1)
[1]
Median progression free survival was not yet reached for 177Lu-DOTA0-Tyr3-Octreotate arm at the time the primary endpoint was evaluated (after 74 events of disease progression or death across study).
2.Secondary Outcome
Title Objective Response Rate (ORR)
Hide Description Objective Response Rate (ORR) is calculated as the proportion of patients whose best overall response is either complete response (CR) or partial response (PR) according to RECIST 1.1.
Time Frame From date of randomization until date of progression or date of death from any cause, whichever come first, assessed up to 5 years (estimated final analysis)
Outcome Measure Data Not Reported
3.Secondary Outcome
Title Overall Survival (OS)
Hide Description Overall Survival (OS) is defined as the time from date of randomization to date of death due to any cause. If a patient was not known to have died by the date of analysis cut-off, OS was censored at the date of last known date patient alive.
Time Frame From date of randomization until date of progression or date of death from any cause, whichever come first, assessed up to 5 years (estimated final analysis)
Outcome Measure Data Not Reported
4.Secondary Outcome
Title Time to Tumour Progression (TTP)
Hide Description Time to Tumour Progression (TTP) is defined as the time from randomization to progression centrally assessed. It includes patients who dropped out due to toxicity, but omits patients who died without measured progression (censored to last follow-up date or death date).
Time Frame From date of randomization until date of progression or date of death from any cause, whichever come first, assessed up to 5 years (estimated final analysis)vidence of tumor progression, assessed for approximately 5 years
Outcome Measure Data Not Reported
5.Secondary Outcome
Title Duration of Response (DoR)
Hide Description The Duration of Response (DoR) is defined as the time from initially meeting the criteria for response (CR or PR) until the time of progression by RECIST.
Time Frame From date of randomization until date of progression or date of death from any cause, whichever come first, assessed up to 5 years (estimated final analysis)
Outcome Measure Data Not Reported
6.Secondary Outcome
Title Number of Participants With Treatment Emergent Adverse Events
Hide Description The distribution of adverse events will be done via the analysis of frequencies for treatment emergent Adverse Event (TEAEs), Serious Adverse Event (TESAEs) and Deaths due to AEs, through the monitoring of relevant clinical and laboratory safety parameters.
Time Frame From date of randomization until 30 day post-treatment safety follow-up, assessed up to 5 years (estimated final OS analysis)
Outcome Measure Data Not Reported
7.Secondary Outcome
Title EORTC QLQ-C30 Questionnaire
Hide Description 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.
Time Frame From date of randomization until 30 day post-treatment safety follow-up, assessed up to 5 years (estimated final OS analysis)
Outcome Measure Data Not Reported
8.Secondary Outcome
Title EORTC Quality of Life Questionnaire - Neuroendocrine Carcinoid Module (EORTC QLQ-GINET21)
Hide Description 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 organized 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.
Time Frame From date of randomization until 30 day post-treatment safety follow-up, assessed up to 5 years (estimated final OS analysis)
Outcome Measure Data Not Reported
Time Frame Adverse event listing based on cutoff date of 30 June 2016, and includes data for 2 patients randomized after primary endpoint cutoff (74 events of PFS) was achieved.
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title 177Lu-DOTA0-Tyr3-Octreotate Octreotide LAR
Hide Arm/Group Description [Not Specified] [Not Specified]
All-Cause Mortality
177Lu-DOTA0-Tyr3-Octreotate Octreotide LAR
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--    
Hide Serious Adverse Events
177Lu-DOTA0-Tyr3-Octreotate Octreotide LAR
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   35/112 (31.25%)      27/111 (24.32%)    
Blood and lymphatic system disorders     
Lymphopenia  1  2/112 (1.79%)  2 0/111 (0.00%)  0
Anemia  1  0/112 (0.00%)  0 1/111 (0.90%)  1
Neutropenia  1  1/112 (0.89%)  1 0/111 (0.00%)  0
Refractory cytopenia with unilineage dysplasia  1  1/112 (0.89%)  1 0/111 (0.00%)  0
Cardiac disorders     
Acute myocardial infarction  1  1/112 (0.89%)  1 0/111 (0.00%)  0
Angina pectoris  1  1/112 (0.89%)  1 0/111 (0.00%)  0
Arteriospasm coronary  1  0/112 (0.00%)  0 1/111 (0.90%)  1
Atrioventricular block second degree  1  1/112 (0.89%)  1 0/111 (0.00%)  0
Cardiac arrest  1  1/112 (0.89%)  1 0/111 (0.00%)  0
Cardiac failure congestive  1  0/112 (0.00%)  0 1/111 (0.90%)  1
Silent myocardial infarction  1  1/112 (0.89%)  1 0/111 (0.00%)  0
Gastrointestinal disorders     
Nausea  1  0/112 (0.00%)  0 1/111 (0.90%)  1
Abdominal Pain  1  3/112 (2.68%)  3 1/111 (0.90%)  1
Diarrhea  1  0/112 (0.00%)  0 1/111 (0.90%)  1
Vomiting  1  2/112 (1.79%)  2 2/111 (1.80%)  2
Ascites  1  1/112 (0.89%)  1 1/111 (0.90%)  1
Haemotochezia  1  1/112 (0.89%)  1 0/111 (0.00%)  0
Small intestinal obstruction  1  1/112 (0.89%)  1 2/111 (1.80%)  2
Abdominal pain lower  1  0/112 (0.00%)  0 2/111 (1.80%)  2
Gastrointestinal obstruction  1  0/112 (0.00%)  0 1/111 (0.90%)  1
Anal hemorrhage  1  0/112 (0.00%)  0 1/111 (0.90%)  1
Duodenal obstruction  1  0/112 (0.00%)  0 1/111 (0.90%)  1
Ileus  1  0/112 (0.00%)  0 1/111 (0.90%)  1
Impaired gastric emptying  1  0/112 (0.00%)  0 1/111 (0.90%)  1
Intestinal obstruction  1  1/112 (0.89%)  1 0/111 (0.00%)  0
Gastritis  1  1/112 (0.89%)  1 0/111 (0.00%)  0
Malignant bowel obstruction  1  0/112 (0.00%)  0 1/111 (0.90%)  1
Oesophagitis  1  0/112 (0.00%)  0 1/111 (0.90%)  1
General disorders     
General physical health deterioration  1  2/112 (1.79%)  2 1/111 (0.90%)  1
Complication of device insertion  1  1/112 (0.89%)  1 0/111 (0.00%)  0
Device occlusion  1  1/112 (0.89%)  1 0/111 (0.00%)  0
Generalized edema  1  0/112 (0.00%)  0 1/111 (0.90%)  1
Injection site hypersensitivity  1  1/112 (0.89%)  1 0/111 (0.00%)  0
Pyrexia  1  1/112 (0.89%)  1 0/111 (0.00%)  0
Hepatobiliary disorders     
Cholecystitis  1  1/112 (0.89%)  1 0/111 (0.00%)  0
Cholecystitis acute  1  0/112 (0.00%)  0 1/111 (0.90%)  1
Cholestasis  1  1/112 (0.89%)  1 0/111 (0.00%)  0
Hepatic encephalopathy  1  1/112 (0.89%)  1 0/111 (0.00%)  0
Hepatocellular injury  1  1/112 (0.89%)  1 0/111 (0.00%)  0
Infections and infestations     
Clostridium difficile infection  1  1/112 (0.89%)  1 0/111 (0.00%)  0
Device related infection  1  1/112 (0.89%)  1 0/111 (0.00%)  0
Diverticulitis  1  1/112 (0.89%)  1 0/111 (0.00%)  0
Pneumocystis jirovecii pneumonia  1  1/112 (0.89%)  1 0/111 (0.00%)  0
Respiratory tract infection  1  1/112 (0.89%)  1 0/111 (0.00%)  0
Sepsis  1  1/112 (0.89%)  1 0/111 (0.00%)  0
Injury, poisoning and procedural complications     
Femur fracture  1  2/112 (1.79%)  2 0/111 (0.00%)  0
Limb injury  1  0/112 (0.00%)  0 1/111 (0.90%)  1
Limb traumatic amputation  1  1/112 (0.89%)  1 0/111 (0.00%)  0
Procedural complication  1  1/112 (0.89%)  1 0/111 (0.00%)  0
Metabolism and nutrition disorders     
Dehydration  1  1/112 (0.89%)  2 1/111 (0.90%)  1
Fluid retention  1  1/112 (0.89%)  1 0/111 (0.00%)  0
Hyperuricaemia  1  0/112 (0.00%)  0 1/111 (0.90%)  1
Hypokalaemia  1  1/112 (0.89%)  1 0/111 (0.00%)  0
Musculoskeletal and connective tissue disorders     
Muscular weakness  1  0/112 (0.00%)  0 1/111 (0.90%)  2
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Malignant neoplasm progression  1  2/112 (1.79%)  2 5/111 (4.50%)  6
Basal cell carcinoma  1  0/112 (0.00%)  0 1/111 (0.90%)  1
Carcinoid crisis  1  0/112 (0.00%)  0 1/111 (0.90%)  1
Diffuse large B-cell lymphoma  1  1/112 (0.89%)  1 0/111 (0.00%)  0
Neoplasm progression  1  0/112 (0.00%)  0 1/111 (0.90%)  1
Oesophageal adenocarcinoma  1  1/112 (0.89%)  1 0/111 (0.00%)  0
Refractory cytopenia with multilineage dysplasia  1  1/112 (0.89%)  1 0/111 (0.00%)  0
Tumor invasion  1  1/112 (0.89%)  1 0/111 (0.00%)  0
Nervous system disorders     
Hemorrhage intracranial  1  0/112 (0.00%)  0 1/111 (0.90%)  1
Syncope  1  0/112 (0.00%)  0 1/111 (0.90%)  1
Thrombotic cerebral infarction  1  0/112 (0.00%)  0 1/111 (0.90%)  1
Transient global amnesia  1  0/112 (0.00%)  0 1/111 (0.90%)  1
Psychiatric disorders     
Anxiety  1  1/112 (0.89%)  1 0/111 (0.00%)  0
Delirium  1  1/112 (0.89%)  1 0/111 (0.00%)  0
Renal and urinary disorders     
Acute kidney injury  1  4/112 (3.57%)  4 1/111 (0.90%)  1
Acute prerenal failure  1  1/112 (0.89%)  1 0/111 (0.00%)  0
Renal impairment  1  0/112 (0.00%)  0 1/111 (0.90%)  1
Respiratory, thoracic and mediastinal disorders     
Acute respiratory failure  1  1/112 (0.89%)  1 0/111 (0.00%)  0
Cough  1  1/112 (0.89%)  1 0/111 (0.00%)  0
Pleural effusion  1  0/112 (0.00%)  0 1/111 (0.90%)  1
Surgical and medical procedures     
Coronary artery bypass  1  1/112 (0.89%)  1 0/111 (0.00%)  0
Vascular disorders     
Inferior vena cava  1  1/112 (0.89%)  1 0/111 (0.00%)  0
Pulmonary embolism  1  1/112 (0.89%)  1 0/111 (0.00%)  0
Shock  1  1/112 (0.89%)  1 0/111 (0.00%)  0
Syncope  1  1/112 (0.89%)  1 0/111 (0.00%)  0
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA Version 18.0
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
177Lu-DOTA0-Tyr3-Octreotate Octreotide LAR
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   110/112 (98.21%)      101/111 (90.99%)    
Blood and lymphatic system disorders     
Anemia  1  18/112 (16.07%)  23 8/111 (7.21%)  10
Lymphopenia  1  18/112 (16.07%)  24 0/111 (0.00%)  0
Thrombocytopenia  1  16/112 (14.29%)  29 0/111 (0.00%)  0
Haematuria  1  7/112 (6.25%)  9 2/111 (1.80%)  2
Gastrointestinal disorders     
Nausea  1  72/112 (64.29%)  161 13/111 (11.71%)  16
Vomiting  1  58/112 (51.79%)  125 9/111 (8.11%)  12
Diarrhoea  1  29/112 (25.89%)  41 19/111 (17.12%)  24
Abdominal pain  1  27/112 (24.11%)  40 20/111 (18.02%)  22
Abdominal distension  1  18/112 (16.07%)  22 14/111 (12.61%)  17
Constipation  1  11/112 (9.82%)  12 6/111 (5.41%)  6
Dyspepsia  1  7/112 (6.25%)  11 7/111 (6.31%)  13
Flatulence  1  6/112 (5.36%)  6 6/111 (5.41%)  6
Abdominal pain upper  1  6/112 (5.36%)  9 2/111 (1.80%)  4
General disorders     
Fatigue  1  42/112 (37.50%)  61 29/111 (26.13%)  31
Oedema peripheral  1  18/112 (16.07%)  25 10/111 (9.01%)  10
Asthenia  1  8/112 (7.14%)  11 8/111 (7.21%)  8
Pyrexia  1  8/112 (7.14%)  10 3/111 (2.70%)  3
Influenza like illness  1  6/112 (5.36%)  13 4/111 (3.60%)  5
Infections and infestations     
Urinary tract infection  1  7/112 (6.25%)  7 7/111 (6.31%)  8
Investigations     
Weight decreased  1  9/112 (8.04%)  11 8/111 (7.21%)  10
Gamma-glutamyltransferase increased  1  7/112 (6.25%)  10 9/111 (8.11%)  10
Blood alkaline phosphatase increased  1  7/112 (6.25%)  8 8/111 (7.21%)  10
Platelet count decreased  1  13/112 (11.61%)  18 2/111 (1.80%)  2
Lymphocyte count decreased  1  12/112 (10.71%)  24 2/111 (1.80%)  2
Blood creatinine increased  1  7/112 (6.25%)  10 6/111 (5.41%)  6
Alanine aminotransferase increased  1  5/112 (4.46%)  5 7/111 (6.31%)  10
Aspartate aminotransferase increased  1  4/112 (3.57%)  5 8/111 (7.21%)  12
Blood bilirubin increased  1  7/112 (6.25%)  9 2/111 (1.80%)  3
White blood cell count decreased  1  7/112 (6.25%)  12 1/111 (0.90%)  2
Hyperglycaemia  1  10/112 (8.93%)  16 10/111 (9.01%)  16
Hypokalaemia  1  8/112 (7.14%)  9 9/111 (8.11%)  11
Hyponatraemia  1  7/112 (6.25%)  8 4/111 (3.60%)  6
Metabolism and nutrition disorders     
Decreased appetite  1  23/112 (20.54%)  35 12/111 (10.81%)  12
Musculoskeletal and connective tissue disorders     
Back pain  1  14/112 (12.50%)  19 11/111 (9.91%)  12
Arthralgia  1  12/112 (10.71%)  16 11/111 (9.91%)  16
Pain in extremity  1  12/112 (10.71%)  15 6/111 (5.41%)  7
Musculoskeletal pain  1  5/112 (4.46%)  5 6/111 (5.41%)  8
Muscle spasms  1  7/112 (6.25%)  11 2/111 (1.80%)  3
Headache  1  19/112 (16.96%)  23 6/111 (5.41%)  28
Dysgeusia  1  9/112 (8.04%)  9 2/111 (1.80%)  3
Syncope  1  6/112 (5.36%)  6 2/111 (1.80%)  2
Nervous system disorders     
Dizziness  1  19/112 (16.96%)  23 9/111 (8.11%)  12
Psychiatric disorders     
Anxiety  1  12/112 (10.71%)  13 6/111 (5.41%)  7
Insomnia  1  3/112 (2.68%)  3 7/111 (6.31%)  12
Respiratory, thoracic and mediastinal disorders     
Dyspnoea  1  12/112 (10.71%)  15 9/111 (8.11%)  11
Cough  1  11/112 (9.82%)  13 7/111 (6.31%)  7
Skin and subcutaneous tissue disorders     
Alopecia  1  13/112 (11.61%)  14 2/111 (1.80%)  2
Vascular disorders     
Flushing  1  16/112 (14.29%)  19 10/111 (9.01%)  12
Hypertension  1  13/112 (11.61%)  20 8/111 (7.21%)  8
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA Version 18.0
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (ie, data from all sites) in the clinical trial.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Study Director
Organization: Novartis Pharmaceuticals
Phone: 862-778-8300
EMail: Novartis.email@novartis.com
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Layout table for additonal information
Responsible Party: Advanced Accelerator Applications
ClinicalTrials.gov Identifier: NCT01578239    
Other Study ID Numbers: AAA-III-01
2011-005049-11 ( EudraCT Number )
CAAA601A12301 ( Other Identifier: Novartis )
First Submitted: April 10, 2012
First Posted: April 16, 2012
Results First Submitted: August 29, 2017
Results First Posted: October 2, 2017
Last Update Posted: March 24, 2021