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 : November 13, 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

Participant Flow

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
Arm/Group Description	Cumulative dose of 29.6 GBq (800 mC...	60 mg Octreotide LAR treatment ever...
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

Baseline Characteristics

Arm/Group Title		177Lu-DOTA0-Tyr3-Octreotate	Octreotide LAR	Total
Arm/Group Description		Cumulative dose of 29.6 GBq (800 mC...	60 mg Octreotide LAR treatment ever...	Total of all reporting groups
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
Baseline Analysis Population Description		...
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

Outcome Measures

1.Primary Outcome


Title	Progression Free Survival (PFS)
Description	Progression is defined u...
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

Outcome Measure Data

Analysis Population Description

Full analysis data set


Arm/Group Title	177Lu-DOTA0-Tyr3-Octreotate	Octreotide LAR
Arm/Group Description:	[Not Specified]	[Not Specified]
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)
Description	The following parameters...
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
Description	Any progressive patient ...
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: 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. 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
Description	...
Description	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

Adverse Events

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
Arm/Group Description	[Not Specified]		[Not Specified]
Arm/Group Description	[Not Specified]		[Not Specified]
All-Cause Mortality
	177Lu-DOTA0-Tyr3-Octreotate		Octreotide LAR
	Affected / at Risk (%)		Affected / at Risk (%)
Total	--/--		--/--
Serious Adverse Events 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
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

Limitations and Caveats

[Not Specified]

More Information

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

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Strosberg J, Wolin E, Chasen B, Kulke M, Bushnell D, Caplin M, Baum RP, Kunz P, Hobday T, Hendifar A, Oberg K, Sierra ML, Thevenet T, Margalet I, Ruszniewski P, Krenning E; NETTER-1 Study Group. Health-Related Quality of Life in Patients With Progressive Midgut Neuroendocrine Tumors Treated With (177)Lu-Dotatate in the Phase III NETTER-1 Trial. J Clin Oncol. 2018 Sep 1;36(25):2578-2584. doi: 10.1200/JCO.2018.78.5865. Epub 2018 Jun 7.

Strosberg J, El-Haddad G, Wolin E, Hendifar A, Yao J, Chasen B, Mittra E, Kunz PL, Kulke MH, Jacene H, Bushnell D, O'Dorisio TM, Baum RP, Kulkarni HR, Caplin M, Lebtahi R, Hobday T, Delpassand E, Van Cutsem E, Benson A, Srirajaskanthan R, Pavel M, Mora J, Berlin J, Grande E, Reed N, Seregni E, Öberg K, Lopera Sierra M, Santoro P, Thevenet T, Erion JL, Ruszniewski P, Kwekkeboom D, Krenning E; NETTER-1 Trial Investigators. Phase 3 Trial of (177)Lu-Dotatate for Midgut Neuroendocrine Tumors. N Engl J Med. 2017 Jan 12;376(2):125-135. doi: 10.1056/NEJMoa1607427.

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 ) 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:	November 13, 2019

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