NCT01578239: NETTER-1

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

Completed Phase 3 Results posted Last updated 4 April 2022

What this trial tests

Phase 3 trial testing Octreotide LAR in Carcinoid Tumor of the Small Bowel in 231 participants. Completed in 18 January 2021.

Timeline

6 September 2012

Primary endpoint
31 July 2015

18 January 2021

Quick facts

Lead sponsor	Advanced Accelerator Applications
Phase	Phase 3
Status	Completed
Study type	INTERVENTIONAL
Allocation	randomized
Design	parallel
Masking	none
Primary purpose	treatment
Enrollment	231
Start date	6 September 2012
Primary completion	31 July 2015
Estimated completion	18 January 2021
Sites	39 locations across France, Italy, Belgium, United Kingdom, Germany, Portugal, United States, Spain

Drugs / interventions tested

• Octreotide LAR — full drug profile →
• 177Lu-DOTA0-Tyr3-Octreotate — full drug profile →

Conditions studied

• Carcinoid Tumor of the Small Bowel — all drugs for Carcinoid Tumor of the Small Bowel →
• Neuroendocrine Tumour — all drugs for Neuroendocrine Tumour →

Sponsor

Advanced Accelerator Applications — full company profile →

Who can join

18 and older, any sex, with Carcinoid Tumor of the Small Bowel or Neuroendocrine Tumour. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Progression Free Survival (PFS) Primary · From date of randomization until date of radiographic progression or date of death from any cause, whichever comes first until Primary Analysis cutoff date reached on 24July2015, assessed up to approximately 34 months

Progression Free Survival (PFS) was defined as the time from randomization to documented centrally assessed disease progression, as evaluated by the Independent Review Committee (IRC), or death due to any cause. If a participant had no centrally assessed progression and had not died at the time of the primary endpoint analysis, the participant was regarded as censored in the context of a time to event analysis at the date of last evaluable tumor assessment. Disease progression was determined by objective tumor response status using Response Evaluation Criteria in Solid Tumors Criteria (RECIST

Group	Value	95% CI
177Lu-DOTA0-Tyr3-Octreotate	NA	NA – NA
Octreotide LAR	8.5	5.8 – 9.1

Objective Response Rate (ORR) Secondary · From date of randomization until date of progression or date of death from any cause, whichever comes first until Primary Analysis cutoff date reached on 24July2015, assessed up to approximately 34 months

Objective Response Rate (ORR) was calculated as the proportion of patients with tumour size reduction (sum of partial responses (PR) and complete responses (CR)) according to RECIST 1.1.

Group	Value	95% CI
177Lu-DOTA0-Tyr3-Octreotate	14.7	7.8 – 21.6
Octreotide LAR	4.0	0.2 – 7.8

Overall Survival (OS) Secondary · From date of randomization until date of death from any cause up to final safety cut-off date reached on 18Jan2021, assessed up to approximately 100 months

Overall Survival (OS) was defined as the time from the date of randomization to the date of death due to any cause or the date of last contact (censored observation) prior to the date of the data cut-off, and during the entire study period (i.e. the treatment period plus follow-up).

Group	Value	95% CI
177Lu-DOTA0-Tyr3-Octreotate	48.0	37.4 – 55.2
Octreotide LAR	36.3	25.9 – 51.7

Rate of Overall Survival (OS) Secondary · 12 months, 24 months, 36 months, 48 months, 60 months

Survival estimates were collected every 12 Months up to 60 Months to compare OS between the two treatment groups.

12 months

Group	Value	95% CI
177Lu-DOTA0-Tyr3-Octreotate	91.0	84.0 – 95.1
Octreotide LAR	79.7	70.8 – 86.1

24 months

Group	Value	95% CI
177Lu-DOTA0-Tyr3-Octreotate	76.0	66.7 – 83.0
Octreotide LAR	62.7	52.6 – 71.2

36 months

Group	Value	95% CI
177Lu-DOTA0-Tyr3-Octreotate	61.4	51.4 – 69.9
Octreotide LAR	50.1	40.0 – 59.4

48 months

Group	Value	95% CI
177Lu-DOTA0-Tyr3-Octreotate	49.5	39.5 – 58.6
Octreotide LAR	41.8	31.8 – 51.4

60 months

Group	Value	95% CI
177Lu-DOTA0-Tyr3-Octreotate	37.1	27.8 – 46.4
Octreotide LAR	35.4	25.7 – 45.2

Time to Tumour Progression (TTP) Secondary · From date of randomization until date of progression or date of death from any cause, whichever comes first until Primary Analysis cutoff date reached on 24July2015, assessed up to approximately 34 months

Time to Tumour Progression (TTP) was defined as the time from randomization to progression centrally assessed. It included patients who dropped out due to toxicity, but omitted patients who died without measured progression (censored to last follow-up date or death date).

Group	Value	95% CI
177Lu-DOTA0-Tyr3-Octreotate	NA	NA – NA
Octreotide LAR	8.7	6.0 – 11.1

Duration of Response (DoR) Secondary · From date of randomization until date of progression or date of death from any cause, whichever comes first until Primary Analysis cutoff date reached on 24July2015, assessed up to approximately 34 months

The Duration of Response (DoR) was defined as the time from initially meeting the criteria for response (CR or PR) until the time of progression by RECIST 1.1.

Group	Value	95% CI
177Lu-DOTA0-Tyr3-Octreotate	NA	2.8 – NA
Octreotide LAR	1.9	1.9 – NA

Number of Participants With Adverse Events Secondary · From informed consent signature through study completion reached at final safety cutoff date on 18July2021, assessed up to approximately 101 Months

The distribution of adverse events was done via the analysis of frequencies for Adverse Event (AEs), Serious Adverse Event (SAEs) and Deaths, through the monitoring of relevant clinical and laboratory safety parameters.

Adverse Events (AEs)

Group	Value	95% CI
177Lu-DOTA0-Tyr3-Octreotate	105
Octreotide LAR	90

Serious Adverse Events (SAEs)

Group	Value	95% CI
177Lu-DOTA0-Tyr3-Octreotate	40
Octreotide LAR	31

Deaths during treatment period

Group	Value	95% CI
177Lu-DOTA0-Tyr3-Octreotate	4
Octreotide LAR	5

Deaths during follow-up period

Group	Value	95% CI
177Lu-DOTA0-Tyr3-Octreotate	66
Octreotide LAR	63

Change From Baseline in the EORTC QLQ-C30 Questionnaire Secondary · Inclusion (Baseline) (BL), Week 72, Week 120

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 transformed so each score ranged a 0-100, where hi

Physical functioning: chg from BL @ wk 72 (n=33,11)

Group	Value	95% CI
177Lu-DOTA0-Tyr3-Octreotate	3.232	± 12.4857
Octreotide LAR	-4.242	± 10.0101

Physical functioning: chg from BL @ wk 120 (n=2,0)

Group	Value	95% CI
177Lu-DOTA0-Tyr3-Octreotate	-3.333	± 4.7140

Role functioning: chg from BL @ wk 72 (n=33,11)

Group	Value	95% CI
177Lu-DOTA0-Tyr3-Octreotate	5.051	± 33.1989
Octreotide LAR	-3.030	± 16.3608

Role functioning: chg from BL @ wk 120 (n=2,0)

Group	Value	95% CI
177Lu-DOTA0-Tyr3-Octreotate	8.333	± 11.7851

Emotional functioning: chg from BL @ wk 72 (n=33,11)

Group	Value	95% CI
177Lu-DOTA0-Tyr3-Octreotate	7.744	± 22.6602
Octreotide LAR	6.061	± 17.9083

Emotional functioning: chg from BL @ wk 120 (n=2,0)

Group	Value	95% CI
177Lu-DOTA0-Tyr3-Octreotate	12.500	± 5.8926

Cognitive functioning: chg from BL @ wk 72 (n=33,11)

Group	Value	95% CI
177Lu-DOTA0-Tyr3-Octreotate	5.556	± 15.9571
Octreotide LAR	1.515	± 13.8535

Cognitive functioning: chg from BL @ wk 120 (n=2,0)

Group	Value	95% CI
177Lu-DOTA0-Tyr3-Octreotate	16.667	± 23.5702

Change From Baseline in the EORTC Quality of Life Questionnaire - Neuroendocrine Carcinoid Module (EORTC QLQ-GINET21) Secondary · Inclusion (Baseline) (BL), Week 72, Week 120

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

Endocrine scale: chg from BL @ wk 72 (n=33,11)

Group	Value	95% CI
177Lu-DOTA0-Tyr3-Octreotate	-8.754	± 20.1762
Octreotide LAR	-11.111	± 21.0819

Endocrine scale: chg from BL @ wk 120 (n=2,0)

Group	Value	95% CI
177Lu-DOTA0-Tyr3-Octreotate	0.000	± 0.0000

G.I. scale: chg from BL @ wk 72 (n=33,11)

Group	Value	95% CI
177Lu-DOTA0-Tyr3-Octreotate	-2.727	± 15.3083
Octreotide LAR	2.424	± 10.0101

G.I. scale: chg from BL @ wk 120 (n=2,0)

Group	Value	95% CI
177Lu-DOTA0-Tyr3-Octreotate	-13.333	± 0.0000

Treatment scale: chg from BL @ wk 72 (n=21,5)

Group	Value	95% CI
177Lu-DOTA0-Tyr3-Octreotate	-8.995	± 14.9563
Octreotide LAR	0.000	± 11.1111

Treatment scale: chg from BL @ wk 120 (n=1,0)

Group	Value	95% CI
177Lu-DOTA0-Tyr3-Octreotate	-16.667	± NA

Social function scale: chg from BL @ wk 72 (n=33,11)

Group	Value	95% CI
177Lu-DOTA0-Tyr3-Octreotate	-7.576	± 23.3985
Octreotide LAR	-7.576	± 21.1217

Social function scale: chg from BL @ wk 120 (n=2,0)

Group	Value	95% CI
177Lu-DOTA0-Tyr3-Octreotate	11.111	± 0.0000

Adverse events — posted to ClinicalTrials.gov

Time frame: From informed consent signature through study completion reached at final safety cutoff date on 18July2021, assessed up to approximately 101 Months.. Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

177Lu-DOTA0-Tyr3-Octreotate

Serious: 40/111 (36%)

Deaths: 70/111

Octreotide LAR

Serious: 31/112 (28%)

Deaths: 68/112

Serious adverse events (88 terms)

Reaction	System	177Lu-DOTA0-Tyr3-Octreotate	Octreotide LAR
Malignant neoplasm progression	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	—	—
Acute kidney injury	Renal and urinary disorders	—	—
Abdominal pain	Gastrointestinal disorders	—	—
Lymphopenia	Blood and lymphatic system disorders	—	—
Abdominal pain lower	Gastrointestinal disorders	—	—
Small intestinal obstruction	Gastrointestinal disorders	—	—
Vomiting	Gastrointestinal disorders	—	—
General physical health deterioration	General disorders	—	—
Femur fracture	Injury, poisoning and procedural complications	—	—
Oesophageal adenocarcinoma	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	—	—
Anaemia	Blood and lymphatic system disorders	—	—
Myelodysplastic syndrome	Blood and lymphatic system disorders	—	—
Neutropenia	Blood and lymphatic system disorders	—	—
Refractory cytopenia with unilineage dysplasia	Blood and lymphatic system disorders	—	—
Acute myocardial infarction	Cardiac disorders	—	—
Angina pectoris	Cardiac disorders	—	—
Arteriospasm coronary	Cardiac disorders	—	—
Atrioventricular block second degree	Cardiac disorders	—	—
Cardiac arrest	Cardiac disorders	—	—
Cardiac failure congestive	Cardiac disorders	—	—
Silent myocardial infarction	Cardiac disorders	—	—
Anal haemorrhage	Gastrointestinal disorders	—	—
Ascites	Gastrointestinal disorders	—	—
Diarrhoea	Gastrointestinal disorders	—	—
Duodenal obstruction	Gastrointestinal disorders	—	—

Other adverse events (50 terms — click to expand)

Reaction	System	177Lu-DOTA0-Tyr3-Octreotate	Octreotide LAR
Nausea	Gastrointestinal disorders	—	—
Vomiting	Gastrointestinal disorders	—	—
Fatigue	General disorders	—	—
Diarrhoea	Gastrointestinal disorders	—	—
Abdominal pain	Gastrointestinal disorders	—	—
Decreased appetite	Metabolism and nutrition disorders	—	—
Headache	Nervous system disorders	—	—
Dizziness	Nervous system disorders	—	—
Anaemia	Blood and lymphatic system disorders	—	—
Lymphopenia	Blood and lymphatic system disorders	—	—
Abdominal distension	Gastrointestinal disorders	—	—
Oedema peripheral	General disorders	—	—
Thrombocytopenia	Blood and lymphatic system disorders	—	—
Flushing	Vascular disorders	—	—
Back pain	Musculoskeletal and connective tissue disorders	—	—
Platelet count decreased	Investigations	—	—
Anxiety	Psychiatric disorders	—	—
Alopecia	Skin and subcutaneous tissue disorders	—	—
Hypertension	Vascular disorders	—	—
Lymphocyte count decreased	Investigations	—	—
Arthralgia	Musculoskeletal and connective tissue disorders	—	—
Pain in extremity	Musculoskeletal and connective tissue disorders	—	—
Cough	Respiratory, thoracic and mediastinal disorders	—	—
Dyspnoea	Respiratory, thoracic and mediastinal disorders	—	—
Constipation	Gastrointestinal disorders	—	—
Hyperglycaemia	Metabolism and nutrition disorders	—	—
Hypokalaemia	Metabolism and nutrition disorders	—	—
Asthenia	General disorders	—	—
Gamma-glutamyltransferase increased	Investigations	—	—
Weight decreased	Investigations	—	—
Dysgeusia	Nervous system disorders	—	—
Pyrexia	General disorders	—	—
Aspartate aminotransferase increased	Investigations	—	—
Blood alkaline phosphatase increased	Investigations	—	—
Insomnia	Psychiatric disorders	—	—
Dyspepsia	Gastrointestinal disorders	—	—
Flatulence	Gastrointestinal disorders	—	—
Urinary tract infection	Infections and infestations	—	—
Alanine aminotransferase increased	Investigations	—	—
Blood bilirubin increased	Investigations	—	—

Most-reported serious reactions: Malignant neoplasm progression, Acute kidney injury, Abdominal pain, Lymphopenia, Abdominal pain lower, Small intestinal obstruction, Vomiting, General physical health deterioration.

Data from ClinicalTrials.gov NCT01578239 adverse events section.

Sponsor's own description

This was a multicenter, stratified, open, randomized, comparator-controlled, parallel-group phase III study comparing treatment with Lutathera plus best supportive care (30 mg Octreotide LAR) to treatment with high dose (60 mg) Octreotide LAR in participants with metastasized or locally advanced, inoperable, somatostatin receptor positive, histologically proven midgut carcinoid tumours with progression despite LAR treatment.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

1. Phase 3 Trial of ¹⁷⁷Lu-Dotatate for Midgut Neuroendocrine Tumors.
   Strosberg J, El-Haddad G, Wolin E, Hendifar A, et al · · 2017 · cited 2312× · PMID 28076709 · DOI 10.1056/nejmoa1607427
2. ENETS Consensus Guidelines Update for the Management of Patients with Functional Pancreatic Neuroendocrine Tumors and Non-Functional Pancreatic Neuroendocrine Tumors.
   Falconi M, Eriksson B, Kaltsas G, Bartsch DK, et al · · 2016 · cited 923× · PMID 26742109 · DOI 10.1159/000443171
3. ¹⁷⁷Lu-Dotatate plus long-acting octreotide versus high‑dose long-acting octreotide in patients with midgut neuroendocrine tumours (NETTER-1): final overall survival and long-term safety results from an open-label, randomised, controlled, phase 3 trial.
   Strosberg JR, Caplin ME, Kunz PL, Ruszniewski PB, et al · · 2021 · cited 393× · PMID 34793718 · DOI 10.1016/s1470-2045(21)00572-6
4. Molecular targeting therapies for neuroblastoma: Progress and challenges.
   Zafar A, Wang W, Liu G, Wang X, et al · · 2021 · cited 291× · PMID 33155698 · DOI 10.1002/med.21750
5. Health-Related Quality of Life in Patients With Progressive Midgut Neuroendocrine Tumors Treated With <sup>177</sup>Lu-Dotatate in the Phase III NETTER-1 Trial.
   Strosberg J, Wolin E, Chasen B, Kulke M, et al · · 2018 · cited 271× · PMID 29878866 · DOI 10.1200/jco.2018.78.5865
6. Peptide-drug conjugates (PDCs): a novel trend of research and development on targeted therapy, hype or hope?
   Fu C, Yu L, Miao Y, Liu X, et al · · 2023 · cited 121× · PMID 36873165 · DOI 10.1016/j.apsb.2022.07.020
7. Targeted Radionuclide Therapy of Human Tumors.
   Gudkov SV, Shilyagina NY, Vodeneev VA, Zvyagin AV. · · 2015 · cited 120× · PMID 26729091 · DOI 10.3390/ijms17010033
8. Impact of liver tumour burden, alkaline phosphatase elevation, and target lesion size on treatment outcomes with <sup>177</sup>Lu-Dotatate: an analysis of the NETTER-1 study.
   Strosberg J, Kunz PL, Hendifar A, Yao J, et al · · 2020 · cited 89× · PMID 32123969 · DOI 10.1007/s00259-020-04709-x