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

NCT01578239 | Completed Phase 3 Results DMC FDA Drug

• 3 other identifiers: AAA-III-012011-005049-11CAAA601A12301
• Study Type: interventional
• Target: 231
• Locations: 8 countries
• Sites: 39

Brief 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, somatostatin receptor positive, histologically proven midgut carcinoid tumours with progression despite LAR treatment.

Conditions

Carcinoid Tumor of the Small Bowel; Neuroendocrine Tumour

Keywords

Neuroendocrine tumour; 177Lu-Dota0-Tyr3-octreotate

Outcome Measures

Primary Outcomes (1)

• 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).

  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)

  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)

  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)

  12 months, 24 months, 36 months, 48 months, 60 months

• Time to Tumour Progression (TTP)

  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)

  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

Study Arms (2)

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.

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.

Drug: Octreotide LAR

Interventions

Octreotide LAR DRUG

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.

Also known as: SANDOSTATIN LAR, Octreotide

177Lu-DOTA0-Tyr3-Octreotate; Octreotide LAR

177Lu-DOTA0-Tyr3-Octreotate DRUG

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.

Also known as: Lutathera

177Lu-DOTA0-Tyr3-Octreotate

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• 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.

You may not qualify if:

• 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.
• 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.

Sponsors & Collaborators

• Advanced Accelerator Applications: lead

Study Sites (39)

Cedars-Sinai Medical Center Samuel Oschin Cancer Center

Los Angeles, California, 90048, United States

Location

Stanford Cancer Center

Palo Alto, California, 94304, United States

Location

Moffitt Cancer Center

Tampa, Florida, 33612, United States

Location

Northwestern Medical Faculty Foundation

Chicago, Illinois, 60611-3015, United States

Location

University of Iowa Hospitals and Clinics

Iowa City, Iowa, 52242, United States

Location

Dana Farber Cancer Institute

Boston, Massachusetts, 02215, United States

Location

Mayo Clinic

Rochester, Minnesota, 55905, United States

Location

Duke University Medical Center

Durham, North Carolina, 27710, United States

Location

Kettering Medical Center

Kettering, Ohio, 45429, United States

Location

Perelman Center for Advanced Medicine

Philadelphia, Pennsylvania, 19104, United States

Location

Henry-Joyce Cancer Clinic

Nashville, Tennessee, 37232, United States

Location

University of Texas MD Anderson Cancer Center

Houston, Texas, 77030, United States

Location

Excel Diagnostics and Nuclear Oncology Center

Houston, Texas, 77042, United States

Location

Digestive Oncology, Leuven Cancer Institute

Leuven, Brabant Flamand, 3000, Belgium

Location

Centre Hospitalier Lyon-Sud

Lyon, Auvergne-Rhône-Alpes, 69002, France

Location

Institut Claudius Regaud

Toulouse, Midi-Pyrénées, 31100, France

Location

Hotel Dieu/CHU Nantes

Nantes, Pays de la Loire Region, 44093, France

Location

Hôpital la Timone /CHU Marseille

Marseille, Provence-Alpes-Côte d'Azur Region, 13385, France

Location

Hôpital Beaujon AP-HP

Clichy, 92118, France

Location

Institut Gustave Roussy

Villejuif, Île-de-France Region, 94805, France

Location

Klinikum Rechts Isar, Nuclear Medicine

Munich, Bavaria, 81675, Germany

Location

Universitätsmedizin Mainz, Medizinische Klinik I Schwerpunkt Endokrinologie

Mainz, Rhineland-Palatinate, 55131, Germany

Location

Zentralklinik Bad Berka

Bad Berka, Thuringia, 99437, Germany

Location

Charité, Virchow-Klinikum, Gastroentrology, Hepatology & Endocrinology

Berlin, 13353, Germany

Location

Istituto Oncologico Romagnolo per lo Studio dei Tumori

Meldola, Emilia-Romagna, 47014, Italy

Location

IEO Istituto Europeo di Oncologia

Milan, Lombardy, 20141, Italy

Location

Presidio Osp. Di Macerata

Macerata, The Marches, 62100, Italy

Location

Azienda Ospedaliero - Universitaria Pisana (Presidio Ospedaliero S. Chiara)

Pisa, Tuscany, 56126, Italy

Location

Fondazione IRCCS Istituto Nazionale dei Tumori

Milan, 20133, Italy

Location

Università "Sapienza" di Roma, Facoltà di Medicina e Psicologia, Ospedale S. Andrea-Roma

Roma, 00189, Italy

Location

Centro Hospitalar e Universitario de Coimbra

Coimbra, Centro, 3000-075, Portugal

Location

Instituto Português de Oncologia

Porto, Norte, 4200-072, Portugal

Location

University Hospital of Bellvitge

Hospitalet de Llobregat (Barcelona), Catalonia, 08907, Spain

Location

Ramon y Cajal University Hospital

Madrid, 28034, Spain

Location

University of Oxford

Oxford, South East England, OX3 7LE, United Kingdom

Location

Beatson Oncology Centre

Glasgow, G12 0YN, United Kingdom

Location

Royal Free Hospital

London, NW3 2QG, United Kingdom

Location

Imperial College Healthcare Trust, Hammersmith Hospital

London, W12 0HS, United Kingdom

Location

The Christie NHS foundation Trust

Manchester, M20 4BX, United Kingdom

Location

Related Publications (4)

• 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.

  PMID: 34793718 DERIVED

• Strosberg 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.

  PMID: 32123969 DERIVED

• 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 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.

  PMID: 29878866 DERIVED

• 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, 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.

  PMID: 28076709 DERIVED

Related Links

• 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)

MeSH Terms

Conditions

Neuroendocrine Tumors

Interventions

Octreotide; lutetium Lu 177 dotatate

Condition Hierarchy (Ancestors)

Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Nerve Tissue

Intervention Hierarchy (Ancestors)

Peptides, Cyclic; Macrocyclic Compounds; Polycyclic Compounds; Peptides; Amino Acids, Peptides, and Proteins

Results Point of Contact

• Title: Study Director
• Organization: Novartis Pharmaceuticals

Novartis.email@novartis.com

862-778-8300

Study Officials

• Novartis Pharmaceuticals

  Novartis Pharmaceuticals

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 10, 2012
• First Posted: April 16, 2012
• Study Start: September 6, 2012
• Primary Completion: July 31, 2015
• Study Completion: January 18, 2021
• Last Updated: April 4, 2022
• Results First Posted: October 2, 2017

Record last verified: 2022-02

Data Sharing

• IPD Sharing: Will share

Locations

US (13); BE (1); DE (4); FR (6); IT (6); GB (5); ES (2); PT (2)