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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 : Active, not recruiting
First Posted : April 16, 2012
Results First Posted : October 2, 2017
Last Update Posted : January 10, 2019
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 116 113
Completed 94 88
Not Completed 22 25
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
United States 66 69 135
Italy 5 9 14
United Kingdom 13 11 24
France 12 9 21
Portugal 1 0 1
Germany 10 7 17
Spain 5 6 11
1.Primary Outcome
Title Progression Free Survival (PFS)
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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 Safety Assessments (Adverse Events, Laboratory Parameters, Cancer Related Symptoms, Physical Examination, Vital Signs, Karnofsky Performance Status, ECG)
Hide Description

The following parameters will be monitored:

  • Changes from Baseline in Hematology (WBC, platelets, haemoglobin, MCV), Blood chemistry (BUN, serum creatinine and creatinine clearance, uric acid, albumin, total bilirubin, AP, aspartate aminotransferase [AST/ASAT], alanine aminotransferase [ALT/ALAT], gamma-glutamyl transferase [γ-GT], [Na], [K], lactic dehydrogenase [LDH], glycosylated hemoglobin/hemoglobin A1c [glycoHb], free thyroxine [fT4]) and Urinalysis (RBC/hpf, WBC/hpf, casts/lpf, protein, 5-HIAA),
  • Cancer related symptoms,
  • Physical Examination, including heart rate, blood pressure and weight,
  • Karnofsky Performance Status,
  • ECG intervals.

All AEs and SAEs reported (spontaneously or not) by the patient will be collected during the study.

Time Frame Data for this outcome measure are posted in the Adverse Events section below. Adverse Events table includes all treatment emergent adverse events collected from date of first enrollment (10 Jul 2012) to 30 June 2016.
Outcome Measure Data Not Reported
3.Secondary Outcome
Title Long-term Safety and Efficacy Assessment
Hide Description

Any progressive patient ceases treatment/assessment and proceeds to long-term follow-up assessment.

Any non-progressive patients continues treatment/assessments until the PFS Primary End-Point, then:

  1. Patients who have 76week or more treatment/assessment stop treatment but continue the long-term follow-up assessments for 5 years overall from the date of randomization of the last randomized.
  2. Remaining randomized patients continue in the fixed 76-week treatment/assessment phase unless progression occurs, then proceed to the long-term follow-up assessment phase for 5 years overall from the date of randomization of the last randomized patient.

During the long-term follow-up assessment phase, toxicities suspected in relation with the study drug (including haematology, biochemistry, urine analyses), anti-tumour treatment administered after progression/discontinuation, disease status based on local CT/MRI assessment, and OS data will be collected every 6 months.

Time Frame Every 6 months for a period of up to 5 years after the end of the study
Outcome Measure Data Not Reported
4.Other Pre-specified Outcome
Title Exploratory Objectives
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  • To explore the correlation of toxicity outcomes and administered radioactivity corrected for body weight and body surface area;
  • To explore the correlation of clinical efficacy outcomes with the levels of the biomarkers Chromogranin-A (CgA) in the serum and 5-Hydroxyindoleacetic acid (5-HIAA) in the urine;
  • To evaluate dosimetry, pharmacokinetics (PK) and ECG in a subset of 20 patients;
  • To explore the correlation of clinical efficacy outcomes with OctreoScan® tumour uptake score;
  • To explore the correlation of clinical outcomes with serum levels of Alkaline Phosphatase (AP):
  • To evaluate the Duration of Response (DoR) in the two study arms;
  • To evaluate the Time to Second Progression (PFS2) in the two study arms
Time Frame Study Treatment Phase
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   --/--      --/--    
Show Serious Adverse Events 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  2/112 (1.79%)  2 0/111 (0.00%)  0
Anemia  0/112 (0.00%)  0 1/111 (0.90%)  1
Neutropenia  1/112 (0.89%)  1 0/111 (0.00%)  0
Refractory cytopenia with unilineage dysplasia  1/112 (0.89%)  1 0/111 (0.00%)  0
Cardiac disorders     
Acute myocardial infarction  1/112 (0.89%)  1 0/111 (0.00%)  0
Angina pectoris  1/112 (0.89%)  1 0/111 (0.00%)  0
Arteriospasm coronary  0/112 (0.00%)  0 1/111 (0.90%)  1
Atrioventricular block second degree  1/112 (0.89%)  1 0/111 (0.00%)  0
Cardiac arrest  1/112 (0.89%)  1 0/111 (0.00%)  0
Cardiac failure congestive  0/112 (0.00%)  0 1/111 (0.90%)  1
Silent myocardial infarction  1/112 (0.89%)  1 0/111 (0.00%)  0
Gastrointestinal disorders     
Nausea  0/112 (0.00%)  0 1/111 (0.90%)  1
Abdominal Pain  3/112 (2.68%)  3 1/111 (0.90%)  1
Diarrhea  0/112 (0.00%)  0 1/111 (0.90%)  1
Vomiting  2/112 (1.79%)  2 2/111 (1.80%)  2
Ascites  1/112 (0.89%)  1 1/111 (0.90%)  1
Haemotochezia  1/112 (0.89%)  1 0/111 (0.00%)  0
Small intestinal obstruction  1/112 (0.89%)  1 2/111 (1.80%)  2
Abdominal pain lower  0/112 (0.00%)  0 2/111 (1.80%)  2
Gastrointestinal obstruction  0/112 (0.00%)  0 1/111 (0.90%)  1
Anal hemorrhage  0/112 (0.00%)  0 1/111 (0.90%)  1
Duodenal obstruction  0/112 (0.00%)  0 1/111 (0.90%)  1
Ileus  0/112 (0.00%)  0 1/111 (0.90%)  1
Impaired gastric emptying  0/112 (0.00%)  0 1/111 (0.90%)  1
Intestinal obstruction  1/112 (0.89%)  1 0/111 (0.00%)  0
Gastritis  1/112 (0.89%)  1 0/111 (0.00%)  0
Malignant bowel obstruction  0/112 (0.00%)  0 1/111 (0.90%)  1
Oesophagitis  0/112 (0.00%)  0 1/111 (0.90%)  1
General disorders     
General physical health deterioration  2/112 (1.79%)  2 1/111 (0.90%)  1
Complication of device insertion  1/112 (0.89%)  1 0/111 (0.00%)  0
Device occlusion  1/112 (0.89%)  1 0/111 (0.00%)  0
Generalized edema  0/112 (0.00%)  0 1/111 (0.90%)  1
Injection site hypersensitivity  1/112 (0.89%)  1 0/111 (0.00%)  0
Pyrexia  1/112 (0.89%)  1 0/111 (0.00%)  0
Hepatobiliary disorders     
Cholecystitis  1/112 (0.89%)  1 0/111 (0.00%)  0
Cholecystitis acute  0/112 (0.00%)  0 1/111 (0.90%)  1
Cholestasis  1/112 (0.89%)  1 0/111 (0.00%)  0
Hepatic encephalopathy  1/112 (0.89%)  1 0/111 (0.00%)  0
Hepatocellular injury  1/112 (0.89%)  1 0/111 (0.00%)  0
Infections and infestations     
Clostridium difficile infection  1/112 (0.89%)  1 0/111 (0.00%)  0
Device related infection  1/112 (0.89%)  1 0/111 (0.00%)  0
Diverticulitis  1/112 (0.89%)  1 0/111 (0.00%)  0
Pneumocystis jirovecii pneumonia  1/112 (0.89%)  1 0/111 (0.00%)  0
Respiratory tract infection  1/112 (0.89%)  1 0/111 (0.00%)  0
Sepsis  1/112 (0.89%)  1 0/111 (0.00%)  0
Injury, poisoning and procedural complications     
Femur fracture  2/112 (1.79%)  2 0/111 (0.00%)  0
Limb injury  0/112 (0.00%)  0 1/111 (0.90%)  1
Limb traumatic amputation  1/112 (0.89%)  1 0/111 (0.00%)  0
Procedural complication  1/112 (0.89%)  1 0/111 (0.00%)  0
Metabolism and nutrition disorders     
Dehydration  1/112 (0.89%)  2 1/111 (0.90%)  1
Fluid retention  1/112 (0.89%)  1 0/111 (0.00%)  0
Hyperuricaemia  0/112 (0.00%)  0 1/111 (0.90%)  1
Hypokalaemia  1/112 (0.89%)  1 0/111 (0.00%)  0
Musculoskeletal and connective tissue disorders     
Muscular weakness  0/112 (0.00%)  0 1/111 (0.90%)  2
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Malignant neoplasm progression  2/112 (1.79%)  2 5/111 (4.50%)  6
Basal cell carcinoma  0/112 (0.00%)  0 1/111 (0.90%)  1
Carcinoid crisis  0/112 (0.00%)  0 1/111 (0.90%)  1
Diffuse large B-cell lymphoma  1/112 (0.89%)  1 0/111 (0.00%)  0
Neoplasm progression  0/112 (0.00%)  0 1/111 (0.90%)  1
Oesophageal adenocarcinoma  1/112 (0.89%)  1 0/111 (0.00%)  0
Refractory cytopenia with multilineage dysplasia  1/112 (0.89%)  1 0/111 (0.00%)  0
Tumor invasion  1/112 (0.89%)  1 0/111 (0.00%)  0
Nervous system disorders     
Hemorrhage intracranial  0/112 (0.00%)  0 1/111 (0.90%)  1
Syncope  0/112 (0.00%)  0 1/111 (0.90%)  1
Thrombotic cerebral infarction  0/112 (0.00%)  0 1/111 (0.90%)  1
Transient global amnesia  0/112 (0.00%)  0 1/111 (0.90%)  1
Psychiatric disorders     
Anxiety  1/112 (0.89%)  1 0/111 (0.00%)  0
Delirium  1/112 (0.89%)  1 0/111 (0.00%)  0
Renal and urinary disorders     
Acute kidney injury  4/112 (3.57%)  4 1/111 (0.90%)  1
Acute prerenal failure  1/112 (0.89%)  1 0/111 (0.00%)  0
Renal impairment  0/112 (0.00%)  0 1/111 (0.90%)  1
Respiratory, thoracic and mediastinal disorders     
Acute respiratory failure  1/112 (0.89%)  1 0/111 (0.00%)  0
Cough  1/112 (0.89%)  1 0/111 (0.00%)  0
Pleural effusion  0/112 (0.00%)  0 1/111 (0.90%)  1
Surgical and medical procedures     
Coronary artery bypass  1/112 (0.89%)  1 0/111 (0.00%)  0
Vascular disorders     
Inferior vena cava  1/112 (0.89%)  1 0/111 (0.00%)  0
Pulmonary embolism  1/112 (0.89%)  1 0/111 (0.00%)  0
Shock  1/112 (0.89%)  1 0/111 (0.00%)  0
Syncope  1/112 (0.89%)  1 0/111 (0.00%)  0
Show Other (Not Including Serious) Adverse Events 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  18/112 (16.07%)  23 8/111 (7.21%)  10
Lymphopenia  18/112 (16.07%)  24 0/111 (0.00%)  0
Thrombocytopenia  16/112 (14.29%)  29 0/111 (0.00%)  0
Haematuria  7/112 (6.25%)  9 2/111 (1.80%)  2
Gastrointestinal disorders     
Nausea  72/112 (64.29%)  161 13/111 (11.71%)  16
Vomiting  58/112 (51.79%)  125 9/111 (8.11%)  12
Diarrhoea  29/112 (25.89%)  41 19/111 (17.12%)  24
Abdominal pain  27/112 (24.11%)  40 20/111 (18.02%)  22
Abdominal distension  18/112 (16.07%)  22 14/111 (12.61%)  17
Constipation  11/112 (9.82%)  12 6/111 (5.41%)  6
Dyspepsia  7/112 (6.25%)  11 7/111 (6.31%)  13
Flatulence  6/112 (5.36%)  6 6/111 (5.41%)  6
Abdominal pain upper  6/112 (5.36%)  9 2/111 (1.80%)  4
General disorders     
Fatigue  42/112 (37.50%)  61 29/111 (26.13%)  31
Oedema peripheral  18/112 (16.07%)  25 10/111 (9.01%)  10
Asthenia  8/112 (7.14%)  11 8/111 (7.21%)  8
Pyrexia  8/112 (7.14%)  10 3/111 (2.70%)  3
Influenza like illness  6/112 (5.36%)  13 4/111 (3.60%)  5
Infections and infestations     
Urinary tract infection  7/112 (6.25%)  7 7/111 (6.31%)  8
Investigations     
Weight decreased  9/112 (8.04%)  11 8/111 (7.21%)  10
Gamma-glutamyltransferase increased  7/112 (6.25%)  10 9/111 (8.11%)  10
Blood alkaline phosphatase increased  7/112 (6.25%)  8 8/111 (7.21%)  10
Platelet count decreased  13/112 (11.61%)  18 2/111 (1.80%)  2
Lymphocyte count decreased  12/112 (10.71%)  24 2/111 (1.80%)  2
Blood creatinine increased  7/112 (6.25%)  10 6/111 (5.41%)  6
Alanine aminotransferase increased  5/112 (4.46%)  5 7/111 (6.31%)  10
Aspartate aminotransferase increased  4/112 (3.57%)  5 8/111 (7.21%)  12
Blood bilirubin increased  7/112 (6.25%)  9 2/111 (1.80%)  3
White blood cell count decreased  7/112 (6.25%)  12 1/111 (0.90%)  2
Hyperglycaemia  10/112 (8.93%)  16 10/111 (9.01%)  16
Hypokalaemia  8/112 (7.14%)  9 9/111 (8.11%)  11
Hyponatraemia  7/112 (6.25%)  8 4/111 (3.60%)  6
Metabolism and nutrition disorders     
Decreased appetite  23/112 (20.54%)  35 12/111 (10.81%)  12
Musculoskeletal and connective tissue disorders     
Back pain  14/112 (12.50%)  19 11/111 (9.91%)  12
Arthralgia  12/112 (10.71%)  16 11/111 (9.91%)  16
Pain in extremity  12/112 (10.71%)  15 6/111 (5.41%)  7
Musculoskeletal pain  5/112 (4.46%)  5 6/111 (5.41%)  8
Muscle spasms  7/112 (6.25%)  11 2/111 (1.80%)  3
Headache  19/112 (16.96%)  23 6/111 (5.41%)  28
Dysgeusia  9/112 (8.04%)  9 2/111 (1.80%)  3
Syncope  6/112 (5.36%)  6 2/111 (1.80%)  2
Nervous system disorders     
Dizziness  19/112 (16.96%)  23 9/111 (8.11%)  12
Psychiatric disorders     
Anxiety  12/112 (10.71%)  13 6/111 (5.41%)  7
Insomnia  3/112 (2.68%)  3 7/111 (6.31%)  12
Respiratory, thoracic and mediastinal disorders     
Dyspnoea  12/112 (10.71%)  15 9/111 (8.11%)  11
Cough  11/112 (9.82%)  13 7/111 (6.31%)  7
Skin and subcutaneous tissue disorders     
Alopecia  13/112 (11.61%)  14 2/111 (1.80%)  2
Vascular disorders     
Flushing  16/112 (14.29%)  19 10/111 (9.01%)  12
Hypertension  13/112 (11.61%)  20 8/111 (7.21%)  8
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.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Paola Santoro, Ph.D., Senior Clinical Study Manager
Organization: Advanced Accelerator Applications
Phone: 917-854-1313
EMail: paola.santoro@adacap.com
Layout table for additonal information
Responsible Party: Advanced Accelerator Applications
ClinicalTrials.gov Identifier: NCT01578239     History of Changes
Other Study ID Numbers: AAA-III-01
2011-005049-11 ( EudraCT Number )
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: January 10, 2019