Carcinoid Tumor of the Small BowelPhase 3NETTER-1NCT01578239
A Study Comparing Treatment With 177Lu-DOTA0-Tyr3-Octreotate to Octreotide LAR in Patients With Inoperable, Progressive, Somatostatin Receptor Positive Midgut Carcinoid Tumours
A Phase 3 study testing Octreotide LAR and 177Lu-DOTA0-Tyr3-Octreotate in people with Carcinoid Tumor of the Small Bowel and Neuroendocrine Tumour, run by Advanced Accelerator Applications at 39 sites in 8 countries.
Trial summary
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… Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Carcinoid Tumor of the Small Bowel, Neuroendocrine Tumour
- What is being tested?
- Octreotide LAR and 177Lu-DOTA0-Tyr3-Octreotate
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 231 participants
- Where
- 39 sitesin 8 countries
- Study dates
- 6 Sep 2012to 18 Jan 2021
- Phase
- Phase 3
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
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
- Presence of metastasized or locally advanced, inoperable (curative intent) at enrollment time, histologically proven, midgut carcinoid tumour (to be centrally confirmed).
- Ki67 index ≤ 20% (to be centrally confirmed).
- Patients on Octreotide LAR at a fixed dose of 20 mg or 30 mg at 3-4 weeks intervals for at least 12 weeks prior to randomization in the study.
- Patients ≥18 years of age.
- Patients must have progressive disease based on RECIST Criteria, Version 1.1 while receiving an uninterrupted fixed dose of Octreotide LAR (20-30 mg/3-4 weeks). Disease progression must be centrally confirmed. In order to make the assessment, two CT (or MRI) scans are required. The oldest scan must not be older than 3 years from the date of randomization. The most recent scan must not be older than 4 weeks from the date of randomization. Both scans must be obtained while the patient is receiving the same fixed dose of Octreotide LAR (20-30 mg/3-4 weeks) with the following exceptions; 1) it is acceptable if the oldest scan is obtained within 12 weeks of the patient receiving a fixed dose regimen of Octreotide LAR (20-30 mg/3-4 weeks); AND 2) it is acceptable for either scan to be obtained before or during the time a patient receiving a fixed dose of Octreotide LAR has switched to an equivalent dose of short acting Octreotide for up to 6 weeks in order to obtain an OctreoScan®, provided the patient returns to the Octreotide LAR fixed dose after the OctreoScan® has been obtained.
- Confirmed presence of somatostatin receptors on all target lesions (for target/non-target/measurable lesions definition see §Appendix 2, Section 1 and 2, RECIST Criteria, Version 1.1) documented by CT/MRI scans, based on positive OctreoScan® imaging within 24 weeks prior to randomization in the study (to be centrally confirmed). The OctreoScan® should be one that was performed while the patient was on a fixed dose of Octreotide LAR. If a patient has had an OctreoScan® performed while Octreotide LAR treatment-naïve, the patient must have a repeat OctreoScan® performed after 3 months of Octreotide LAR treatments before entering the clinical study to prove that the index lesions or new lesions still meet the criteria for inclusion. It is acceptable to have patients temporarily switched to Octreotide s.c. (up to six weeks) in order to obtain an OctreoScan®, provided they return to the same fixed dose of Octreotide LAR prior to the scan.
Show all 10Show fewer
- The tumour uptake observed in each target lesion (for target/non-target/measurable lesions definition see §Appendix 2, Sections 1 and 2, RECIST Criteria, Version 1.1) using OctreoScan® must be ≥ normal liver uptake observed on planar imaging (to be centrally confirmed) (§Appendices 5 and 6).
- Karnofsky Performance Score (KPS)>=60.
- Presence of at least 1 measurable site of disease.
- [Applicable only for France] All patients included in the trial must be affiliated with a social security regime or be a beneficiary of the same in order to be included in the study.
Who cannot join
- Either serum creatinine >150 µmol/L (>1.7 mg/dL), or creatinine clearance <50 mL/min calculated by the Cockroft Gault method, eventually confirmed by measured creatinine clearance (or measured glomerular filtration rate (GFR) using plasma clearance methods, not gamma camera-based) <50 mL/min (the measured creatinine clearance / GFR is required only as confirmatory exam).
- Hb concentration <5.0 mmol/L (<8.0 g/dL); WBC <2x109/L (2000/mm3); platelets <75x109/L (75x103/mm3).
- Total bilirubin >3 x ULN.
- Serum albumin <3.0 g/dL unless prothrombin time is within the normal range.
- Pregnancy or lactation.
- For female patients of childbearing potential (defined as < 2 years after last menstruation and not surgically sterile) and male patients, who are not surgically sterile or with female partners of childbearing potential: absence of effective, non-hormonal means of contraception (intrauterine contraceptive device, barrier method of contraception in conjunction with spermicidal gel) as defined in §Appendix 7.
Show all 21Show fewer
- Treatment with >30 mg Octreotide LAR at 3-4 weeks intervals within 12 weeks prior to randomization in the study.
- Peptide receptor radionuclide therapy (PRRT) at any time prior to randomization in the study.
- Any surgery, radioembolization, chemoembolization, chemotherapy and radiofrequency ablation within 12 weeks prior to randomization in the study.
- Interferons, Everolimus (mTOR-inhibitors) or other systemic therapies within 4 weeks prior to randomization in the study.
- Known brain metastases, unless these metastases have been treated and stabilized for at least 24 weeks, prior to enrollment in the study. Patients with a history of brain metastases must have a head CT with contrast to document stable disease prior to randomization in the study.
- Uncontrolled congestive heart failure (NYHA II, III, IV).
- Uncontrolled diabetes mellitus as defined by a fasting blood glucose >2 ULN.
- Any patient receiving treatment with short-acting Octreotide, which cannot be interrupted for 24 h before and 24 h after the administration of 177Lu-DOTA0-Tyr3-Octreotate, or any patient receiving treatment with Octreotide LAR, which cannot be interrupted for at least 6 weeks before the administration of 177Lu-DOTA0-Tyr3-Octreotate, unless the tumour uptake on target lesions observed by OctreoScan® imaging during continued Octreotide LAR treatment is at least as high as normal liver uptake observed by planar imaging.
- Patients with any other significant medical, psychiatric, or surgical condition, currently uncontrolled by treatment, which may interfere with the completion of the study.
- Prior external beam radiation therapy to more than 25% of the bone marrow.
- Current spontaneous urinary incontinence.
- Other known co-existing malignancies except non-melanoma skin cancer and carcinoma in situ of the uterine cervix, unless definitively treated and proven no evidence of recurrence for 5 years.
- Patients who have not provided a signed informed consent form to participate in the study, obtained prior to the start of any protocol related activities.
- Patient with known incompatibility to CT Scans with I.V. contrast due to allergic reaction or renal insufficiency. If such a patient can be imaged with MRI, then the patient would not be excluded.
- Patients who have participated in any therapeutic clinical study/received any investigational agent within the last 30 days are excluded from participation in this trial.
Trial locations and contacts
39 sites in 8 countries.
39 sites in 8 countries
United States13 sites
Dana Farber Cancer Institute
Boston, Massachusetts, 02215
Northwestern Medical Faculty Foundation
Chicago, Illinois, 60611-3015
Duke University Medical Center
Durham, North Carolina, 27710
University of Texas MD Anderson Cancer Center
Houston, Texas, 77030
Excel Diagnostics and Nuclear Oncology Center
Houston, Texas, 77042
University of Iowa Hospitals and Clinics
Iowa City, Iowa, 52242
Kettering Medical Center
Kettering, Ohio, 45429
Cedars-Sinai Medical Center Samuel Oschin Cancer Center
Los Angeles, California, 90048
Henry-Joyce Cancer Clinic
Nashville, Tennessee, 37232
Stanford Cancer Center
Palo Alto, California, 94304
Perelman Center for Advanced Medicine
Philadelphia, Pennsylvania, 19104
Mayo Clinic
Rochester, Minnesota, 55905
Moffitt Cancer Center
Tampa, Florida, 33612
France6 sites
Hôpital Beaujon AP-HP
Clichy, 92118
Centre Hospitalier Lyon-Sud
Lyon, Auvergne-Rhône-Alpes, 69002
Hôpital la Timone /CHU Marseille
Marseille, Provence-Alpes-Côte d'Azur Region, 13385
Hotel Dieu/CHU Nantes
Nantes, Pays de la Loire Region, 44093
Institut Claudius Regaud
Toulouse, Midi-Pyrénées, 31100
Institut Gustave Roussy
Villejuif, Île-de-France Region, 94805
Italy6 sites
Istituto Oncologico Romagnolo per lo Studio dei Tumori
Meldola, Emilia-Romagna, 47014
IEO Istituto Europeo di Oncologia
Milan, Lombardy, 20141
Fondazione IRCCS Istituto Nazionale dei Tumori
Milan, 20133
Azienda Ospedaliero - Universitaria Pisana (Presidio Ospedaliero S. Chiara)
Pisa, Tuscany, 56126
Presidio Osp. Di Macerata
Province of Macerata, The Marches, 62100
Università "Sapienza" di Roma, Facoltà di Medicina e Psicologia, Ospedale S. Andrea-Roma
Roma, 00189
United Kingdom5 sites
Beatson Oncology Centre
Glasgow, G12 0YN
Royal Free Hospital
London, NW3 2QG
Imperial College Healthcare Trust, Hammersmith Hospital
London, W12 0HS
The Christie NHS foundation Trust
Manchester, M20 4BX
University of Oxford
Oxford, South East England, OX3 7LE
Germany4 sites
Zentralklinik Bad Berka
Bad Berka, Thuringia, 99437
Charité, Virchow-Klinikum, Gastroentrology, Hepatology & Endocrinology
Berlin, 13353
Universitätsmedizin Mainz, Medizinische Klinik I Schwerpunkt Endokrinologie
Mainz, Rhineland-Palatinate, 55131
Klinikum Rechts Isar, Nuclear Medicine
Munich, Bavaria, 81675
Portugal2 sites
Centro Hospitalar e Universitario de Coimbra
Coimbra, Centro, 3000-075
Instituto Português de Oncologia
Porto, Norte, 4200-072
Spain2 sites
University Hospital of Bellvitge
Hospitalet de Llobregat (Barcelona), Catalonia, 08907
Ramon y Cajal University Hospital
Madrid, 28034
Belgium1 site
Digestive Oncology, Leuven Cancer Institute
Leuven, Brabant Flamand, 3000
About this study
Official title: A Multicentre, Stratified, Open, Randomized, Comparator-controlled, Parallel-group Phase III Study Comparing Treatment With 177Lu-DOTA0-Tyr3-Octreotate to Octreotide LAR in Patients With Inoperable, Progressive, Somatostatin Receptor Positive Midgut Carcinoid Tumours
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.
Read the detailed description
After the screening period, participants who signed the ICF and were eligible for the study in accordance with the entry criteria were randomly assigned to treatment either Lutathera or Octreotide LAR. Participant randomization was performed according to a centralized permuted block randomization scheme with a balanced ratio (1:1) between the 2 treatment groups, stratified by tumor uptake score and by the length of time that a participant was on a constant dose of Octreotide (=< 6 versus > 6 months).
Objective tumor assessment in both groups was performed every 12+/-1 weeks from the randomization date according to RECIST Criteria until progression was centrally confirmed:
- Any participants with progressive disease (confirmed by central review of CT/MRI scans) ceased the treatment/assessment period and proceeded to the long-term follow-up period for evaluation of survival and long-term safety.
- All non-progressive participants continued treatment/assessments until the PFS primary endpoint was met (i.e. 74 evaluable and centrally confirmed disease progressions or death events). Once the Primary End-Point was reached:
- Participants who received more than 76 weeks of treatment/assessment, stopped the study treatment (however somatostatin analogues could be received as subsequent treatment as per Investigator's discretion) but continued the long-term follow-up assessment for 5 years overall from the date of randomization of the last participant randomized.
- The remaining randomized participants continued in the fixed 76-week treatment/assessment period unless progression occurred, then continued the long-term follow-up assessments for 5 years overall from the date of randomization of the last participant.
- Being tested
- Octreotide LAR, 177Lu-DOTA0-Tyr3-Octreotate
- Keywords
- Neuroendocrine tumour, 177Lu-Dota0-Tyr3-octreotate
- Medical subject headings
- Neuroendocrine Tumors
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Octreotide LARDrug
Also called SANDOSTATIN LAR, Octreotide
In the experimental arm, 30 mg Octreotide LAR treatment was given to the participants until the end of study for symptom control purpose, unless the participant progressed or died.
In the active comparator arm, 60 mg Octreotide LAR treatment was given to the participants every 4 weeks (i.m. injections) until the end of the study, unless the participant progressed or died.
177Lu-DOTA0-Tyr3-OctreotateDrug
Also called Lutathera
Four administrations of 7.4 GBq (200 mCi) 177Lu-DOTA0-Tyr3-Octreotate administered at 8 +/- 1-week intervals, which could be extended up to 16 weeks to accommodate resolving acute toxicity.
| Study group | Role | What they receive |
|---|---|---|
| 177Lu-DOTA0-Tyr3-Octreotate | Experimental | * 30 mg Octreotide LAR treatment for symptom control continued until the end of study, unless the participant progressed or died.
* Treatment consisted of a cumulative administered radioactivity of 29.6 Giga Becquerel (GBq) (800 mCi) 177Lu-DOTA0-Tyr3-Octreotate: Four administrations of 7.4 GBq (200 mCi).
* Concomitant amino acids were given with each administration for kidney protection.
* 177Lu-DOTA0-Tyr3-Octreotate was administered at 8 +/- 1-week intervals, which could be extended up to 16 weeks to accommodate resolving acute toxicity.
* In case participants experienced clinical symptoms (i.e. diarrhoea and flushing) associated with their carcinoid tumours, Octreotide s.c. rescue injections were allowed. Receives: Drug: Octreotide LAR; Drug: 177Lu-DOTA0-Tyr3-Octreotate |
| Octreotide LAR | Active comparator | * 60 mg Octreotide LAR treatment every 4 weeks (i.m. injections) until the end of the study, unless the participant progressed or died.
* In case participants experienced clinical symptoms (i.e. diarrhoea and flushing) associated with their carcinoid tumours, s.c. Octreotide rescue injections were allowed. Receives: Drug: Octreotide LAR |
What is being measured
The primary outcome is the main question the study is designed to answer.
Progression Free Survival (PFS)
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 v1.1).
Measured: 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
Secondary outcomes (8)
Objective Response Rate (ORR)
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.
Measured: 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
Overall Survival (OS)
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).
Measured: 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
Rate of Overall Survival (OS)
Survival estimates were collected every 12 Months up to 60 Months to compare OS between the two treatment groups.
Measured: 12 months, 24 months, 36 months, 48 months, 60 months
Time to Tumour Progression (TTP)
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).
Measured: 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
Duration of Response (DoR)
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.
Measured: 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
Number of Participants With Adverse Events
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.
Measured: From informed consent signature through study completion reached at final safety cutoff date on 18July2021, assessed up to approximately 101 Months
Change From Baseline in the EORTC QLQ-C30 Questionnaire
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 higher scores indicate worse symptoms (e.g., more severe/worsened) and lower scores indicate less symptoms (e.g., less severe/improvement).
Measured: Inclusion (Baseline) (BL), Week 72, Week 120
Change From Baseline in the EORTC Quality of Life Questionnaire - Neuroendocrine Carcinoid Module (EORTC QLQ-GINET21)
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.
Measured: Inclusion (Baseline) (BL), Week 72, Week 120
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted16 Apr 2012 (estimated)
- Study start6 Sep 2012
- Primary completion31 Jul 2015
- Study completion18 Jan 2021
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (4)Papers the sponsor has linked to this study.
- Other trials for Carcinoid Tumor of the Small BowelStudies of the same condition, open and under way.
- 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
- None (open label)
- Enrolment
- 231 participants (actual)
Sponsor and investigators
- Lead sponsor
- Advanced Accelerator Applications
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- Novartis Pharmaceuticals, Study director, Novartis Pharmaceuticals
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01578239
- Sponsor's protocol ID
- AAA-III-01
- Other IDs
- 2011-005049-11, CAAA601A12301
- Acronym
- NETTER-1
- Status last verified
- Feb 2022
- First submitted
- 10 Apr 2012
- Last updated
- 4 Apr 2022
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes: Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations. This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com
Publications
Strosberg JR, Caplin ME, Kunz PL, Ruszniewski PB, Bodei L, Hendifar A, Mittra E, Wolin EM, Yao JC, Pavel ME, Grande E, Van Cutsem E, Seregni E, Duarte H, Gericke G, Bartalotta A, Mariani MF, Demange A, Mutevelic S, Krenning EP; NETTER-1 investigators. 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. Lancet Oncol. 2021 Dec;22(12):1752-1763. doi: 10.1016/S1470-2045(21)00572-6. Epub 2021 Nov 15.
PubMed 34793718Strosberg J, Kunz PL, Hendifar A, Yao J, Bushnell D, Kulke MH, Baum RP, Caplin M, Ruszniewski P, Delpassand E, Hobday T, Verslype C, Benson A, Srirajaskanthan R, Pavel M, Mora J, Berlin J, Grande E, Reed N, Seregni E, Paganelli G, Severi S, Morse M, Metz DC, Ansquer C, Courbon F, Al-Nahhas A, Baudin E, Giammarile F, Taieb D, Mittra E, Wolin E, O'Dorisio TM, Lebtahi R, Deroose CM, Grana CM, Bodei L, Oberg K, Polack BD, He B, Mariani MF, Gericke G, Santoro P, Erion JL, Ravasi L, Krenning E; NETTER-1 study group. Impact of liver tumour burden, alkaline phosphatase elevation, and target lesion size on treatment outcomes with 177Lu-Dotatate: an analysis of the NETTER-1 study. Eur J Nucl Med Mol Imaging. 2020 Sep;47(10):2372-2382. doi: 10.1007/s00259-020-04709-x. Epub 2020 Mar 2.
PubMed 32123969Strosberg 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 177Lu-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.
PubMed 29878866Strosberg 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, Oberg K, Lopera Sierra M, Santoro P, Thevenet T, Erion JL, Ruszniewski P, Kwekkeboom D, Krenning E; NETTER-1 Trial Investigators. Phase 3 Trial of 177Lu-Dotatate for Midgut Neuroendocrine Tumors. N Engl J Med. 2017 Jan 12;376(2):125-135. doi: 10.1056/NEJMoa1607427.
PubMed 28076709
Study at a glance
From the registry record, last updated by the sponsor on 4 Apr 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Multicentre, Stratified, Open, Randomized, Comparator-controlled, Parallel-group Phase III Study Comparing Treatment With 177Lu-DOTA0-Tyr3-Octreotate to Octreotide LAR in Patients With Inoperable, Progressive, Somatostatin Receptor Positive Midgut Carcinoid Tumours
- ClinicalTrials.gov ID
- NCT01578239
- Acronym / sponsor ID
- NETTER-1 / AAA-III-01
- Keywords
- Neuroendocrine tumour, 177Lu-Dota0-Tyr3-octreotate
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 231 participants (actual)
- Lead sponsor
- Advanced Accelerator ApplicationsIndustry (pharma, biotech, devices)
- Study start
- 6 Sep 2012 (actual)
- Primary completion
- 31 Jul 2015 (actual)
- Study completion
- 18 Jan 2021 (actual)
- First posted
- 16 Apr 2012 (estimated)
- Results
- Posted 2 Oct 2017
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
After the screening period, participants who signed the ICF and were eligible for the study in accordance with the entry criteria were randomly assigned to treatment either Lutathera or Octreotide LAR. Participant randomization was performed according to a centralized permuted block randomization scheme with a balanced ratio (1:1) between the 2 treatment groups, stratified by tumor uptake score and by the length of time that a participant was on a constant dose of Octreotide (=< 6 versus > 6 months).
Objective tumor assessment in both groups was performed every 12+/-1 weeks from the randomization date according to RECIST Criteria until progression was centrally confirmed:
- Any participants with progressive disease (confirmed by central review of CT/MRI scans) ceased the treatment/assessment period and proceeded to the long-term follow-up period for evaluation of survival and long-term safety.
- All non-progressive participants continued treatment/assessments until the PFS primary endpoint was met (i.e. 74 evaluable and centrally confirmed disease progressions or death events). Once the Primary End-Point was reached:
- Participants who received more than 76 weeks of treatment/assessment, stopped the study treatment (however somatostatin analogues could be received as subsequent treatment as per Investigator's discretion) but continued the long-term follow-up assessment for 5 years overall from the date of randomization of the last participant randomized.
- The remaining randomized participants continued in the fixed 76-week treatment/assessment period unless progression occurred, then continued the long-term follow-up assessments for 5 years overall from the date of randomization of the last participant.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| 177Lu-DOTA0-Tyr3-Octreotate | Experimental | Drug: Octreotide LAR, Drug: 177Lu-DOTA0-Tyr3-Octreotate* 30 mg Octreotide LAR treatment for symptom control continued until the end of study, unless the participant progressed or died. * Treatment consisted of a cumulative administered radioactivity of 29.6 Giga Becquerel (GBq) (800 mCi) 177Lu-DOTA0-Tyr3-Octreotate: Four administrations of 7.4 GBq (200 mCi). * Concomitant amino acids were given with each administration for kidney protection. * 177Lu-DOTA0-Tyr3-Octreotate was administered at 8 +/- 1-week intervals, which could be extended up to 16 weeks to accommodate resolving acute toxicity. * In case participants experienced clinical symptoms (i.e. diarrhoea and flushing) associated with their carcinoid tumours, Octreotide s.c. rescue injections were allowed. |
| Octreotide LAR | Active comparator | Drug: Octreotide LAR* 60 mg Octreotide LAR treatment every 4 weeks (i.m. injections) until the end of the study, unless the participant progressed or died. * In case participants experienced clinical symptoms (i.e. diarrhoea and flushing) associated with their carcinoid tumours, s.c. Octreotide rescue injections were allowed. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (10 listed)
- Presence of metastasized or locally advanced, inoperable (curative intent) at enrollment time, histologically proven, midgut carcinoid tumour (to be centrally confirmed).
- Ki67 index ≤ 20% (to be centrally confirmed).
- Patients on Octreotide LAR at a fixed dose of 20 mg or 30 mg at 3-4 weeks intervals for at least 12 weeks prior to randomization in the study.
- Patients ≥18 years of age.
- Patients must have progressive disease based on RECIST Criteria, Version 1.1 while receiving an uninterrupted fixed dose of Octreotide LAR (20-30 mg/3-4 weeks). Disease progression must be centrally confirmed. In order to make the assessment, two CT (or MRI) scans are required. The oldest scan must not be older than 3 years from the date of randomization. The most recent scan must not be older than 4 weeks from the date of randomization. Both scans must be obtained while the patient is receiving the same fixed dose of Octreotide LAR (20-30 mg/3-4 weeks) with the following exceptions; 1) it is acceptable if the oldest scan is obtained within 12 weeks of the patient receiving a fixed dose regimen of Octreotide LAR (20-30 mg/3-4 weeks); AND 2) it is acceptable for either scan to be obtained before or during the time a patient receiving a fixed dose of Octreotide LAR has switched to an equivalent dose of short acting Octreotide for up to 6 weeks in order to obtain an OctreoScan®, provided the patient returns to the Octreotide LAR fixed dose after the OctreoScan® has been obtained.
Key exclusion criteria (21 listed)
- Either serum creatinine >150 µmol/L (>1.7 mg/dL), or creatinine clearance <50 mL/min calculated by the Cockroft Gault method, eventually confirmed by measured creatinine clearance (or measured glomerular filtration rate (GFR) using plasma clearance methods, not gamma camera-based) <50 mL/min (the measured creatinine clearance / GFR is required only as confirmatory exam).
- Hb concentration <5.0 mmol/L (<8.0 g/dL); WBC <2x109/L (2000/mm3); platelets <75x109/L (75x103/mm3).
- Total bilirubin >3 x ULN.
- Serum albumin <3.0 g/dL unless prothrombin time is within the normal range.
- Pregnancy or lactation.
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 |
|---|---|---|
| Octreotide LARAlso: SANDOSTATIN LAR, OctreotideIn the experimental arm, 30 mg Octreotide LAR treatment was given to the participants until the end of study for symptom control purpose, unless the participant progressed or died. In the active comparator arm, 60 mg Octreotide LAR treatment was given to the participants every 4 weeks (i.m. injections) until the end of the study, unless the participant progressed or died. | Drug | 177Lu-DOTA0-Tyr3-Octreotate, Octreotide LAR |
| 177Lu-DOTA0-Tyr3-OctreotateAlso: LutatheraFour administrations of 7.4 GBq (200 mCi) 177Lu-DOTA0-Tyr3-Octreotate administered at 8 +/- 1-week intervals, which could be extended up to 16 weeks to accommodate resolving acute toxicity. | Drug | 177Lu-DOTA0-Tyr3-Octreotate |
Primary outcome
Progression Free Survival (PFS)
Time frame: 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 v1.1).
8 secondary outcomes
Objective Response Rate (ORR)
Time frame: 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
Overall Survival (OS)
Time frame: 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
Rate of Overall Survival (OS)
Time frame: 12 months, 24 months, 36 months, 48 months, 60 months
Time to Tumour Progression (TTP)
Time frame: 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
Duration of Response (DoR)
Time frame: 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
Number of Participants With Adverse Events
Time frame: From informed consent signature through study completion reached at final safety cutoff date on 18July2021, assessed up to approximately 101 Months
Change From Baseline in the EORTC QLQ-C30 Questionnaire
Time frame: Inclusion (Baseline) (BL), Week 72, Week 120
Change From Baseline in the EORTC Quality of Life Questionnaire - Neuroendocrine Carcinoid Module (EORTC QLQ-GINET21)
Time frame: Inclusion (Baseline) (BL), Week 72, Week 120
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 4 Apr 2022.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 34793718Strosberg JR, Caplin ME, Kunz PL, Ruszniewski PB, Bodei L, Hendifar A, Mittra E, Wolin EM, Yao JC, Pavel ME, Grande E, Van Cutsem E, Seregni E, Duarte H, Gericke G, Bartalotta A, Mariani MF, Demange A, Mutevelic S, Krenning EP; NETTER-1 investigators. 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. Lancet Oncol. 2021 Dec;22(12):1752-1763. doi: 10.1016/S1470-2045(21)00572-6. Epub 2021 Nov 15.
- Derived from this study: PubMed 32123969Strosberg J, Kunz PL, Hendifar A, Yao J, Bushnell D, Kulke MH, Baum RP, Caplin M, Ruszniewski P, Delpassand E, Hobday T, Verslype C, Benson A, Srirajaskanthan R, Pavel M, Mora J, Berlin J, Grande E, Reed N, Seregni E, Paganelli G, Severi S, Morse M, Metz DC, Ansquer C, Courbon F, Al-Nahhas A, Baudin E, Giammarile F, Taieb D, Mittra E, Wolin E, O'Dorisio TM, Lebtahi R, Deroose CM, Grana CM, Bodei L, Oberg K, Polack BD, He B, Mariani MF, Gericke G, Santoro P, Erion JL, Ravasi L, Krenning E; NETTER-1 study group. Impact of liver tumour burden, alkaline phosphatase elevation, and target lesion size on treatment outcomes with 177Lu-Dotatate: an analysis of the NETTER-1 study. Eur J Nucl Med Mol Imaging. 2020 Sep;47(10):2372-2382. doi: 10.1007/s00259-020-04709-x. Epub 2020 Mar 2.
- Derived from this study: PubMed 29878866Strosberg 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 177Lu-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.
- Derived from this study: PubMed 28076709Strosberg 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, Oberg K, Lopera Sierra M, Santoro P, Thevenet T, Erion JL, Ruszniewski P, Kwekkeboom D, Krenning E; NETTER-1 Trial Investigators. Phase 3 Trial of 177Lu-Dotatate for Midgut Neuroendocrine Tumors. N Engl J Med. 2017 Jan 12;376(2):125-135. doi: 10.1056/NEJMoa1607427.
- NETTER-1 first interpretable study results published in the New England Journal of Medicine in January 2017Link provided by the sponsor.
- 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)Link provided by the sponsor.
- Individual participant dataSharing planned: Yes. Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations. This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com
Related trials for Carcinoid Tumor of the Small Bowel
Recruiting
Virtual Reality for GI Cancer Pain to Improve Patient Reported Outcomes
Cancer Pain, Visceral Pain
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.
Novartis Pharmaceuticals study director
Novartis Pharmaceuticals
39 sites in 8 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Octreotide LAR and 177Lu-DOTA0-Tyr3-Octreotate in people with Carcinoid Tumor of the Small Bowel and Neuroendocrine Tumour, run by Advanced Accelerator Applications at 39 sites in 8 countries.
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 10 inclusion and 21 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: finished, as of the sponsor's last update on 4 Apr 2022. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 39 sites in United States, France, Italy, United Kingdom, Germany and 3 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. 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?
Yes. Results are posted in the registry (first posted 2 Oct 2017). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
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?
Progression Free Survival (PFS) (time frame: 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). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01578239, which also lists 4 linked publications.
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 4 Apr 2022.