Clinical trial NCT01578239: A Study Comparing Treatment With 177Lu-DOTA0-Tyr3-Octreotate to Octreotide LAR in Patients With Inoperable, Progressive, Somatostatin Receptor Positive Midgut Carcinoid Tumours
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Carcinoid Tumor of the Small Bowel
Neuroendocrine Tumour
Keywords: Neuroendocrine tumour
177Lu-Dota0-Tyr3-octreotate
Lead sponsor: Advanced Accelerator Applications
Sponsor class: INDUSTRY
First posted: 2012-04-16
Enrollment: 231
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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:

1. 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.
2. 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:

   1. 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.
   2. 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.

Eligibility criteria: Inclusion Criteria:

1. Presence of metastasized or locally advanced, inoperable (curative intent) at enrollment time, histologically proven, midgut carcinoid tumour (to be centrally confirmed).
2. Ki67 index ≤ 20% (to be centrally confirmed).
3. 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.
4. Patients ≥18 years of age.
5. 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.
6. 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.
7. 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).
8. Karnofsky Performance Score (KPS)\>=60.
9. Presence of at least 1 measurable site of disease.
10. \[Applicable only for France\] 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.

Exclusion Criteria:

1. 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).
2. Hb concentration \<5.0 mmol/L (\<8.0 g/dL); WBC \<2x109/L (2000/mm3); platelets \<75x109/L (75x103/mm3).
3. Total bilirubin \>3 x ULN.
4. Serum albumin \<3.0 g/dL unless prothrombin time is within the normal range.
5. Pregnancy or lactation.
6. 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.
7. Treatment with \>30 mg Octreotide LAR at 3-4 weeks intervals within 12 weeks prior to randomization in the study.
8. Peptide receptor radionuclide therapy (PRRT) at any time prior to randomization in the study.
9. Any surgery, radioembolization, chemoembolization, chemotherapy and radiofrequency ablation within 12 weeks prior to randomization in the study.
10. Interferons, Everolimus (mTOR-inhibitors) or other systemic therapies within 4 weeks prior to randomization in the study.
11. 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.
12. Uncontrolled congestive heart failure (NYHA II, III, IV).
13. Uncontrolled diabetes mellitus as defined by a fasting blood glucose \>2 ULN.
14. 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.
15. Patients with any other significant medical, psychiatric, or surgical condition, currently uncontrolled by treatment, which may interfere with the completion of the study.
16. Prior external beam radiation therapy to more than 25% of the bone marrow.
17. Current spontaneous urinary incontinence.
18. 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.
19. 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.
20. 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.
21. 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.

Primary outcomes:
measure: Progression Free Survival (PFS)
timeFrame: 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:
measure: Objective Response Rate (ORR)
timeFrame: 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
measure: Overall Survival (OS)
timeFrame: 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
measure: Rate of Overall Survival (OS)
timeFrame: 12 months, 24 months, 36 months, 48 months, 60 months
measure: Time to Tumour Progression (TTP)
timeFrame: 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
measure: Duration of Response (DoR)
timeFrame: 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
measure: Number of Participants With Adverse Events
timeFrame: From informed consent signature through study completion reached at final safety cutoff date on 18July2021, assessed up to approximately 101 Months
measure: Change From Baseline in the EORTC QLQ-C30 Questionnaire
timeFrame: Inclusion (Baseline) (BL), Week 72, Week 120
measure: Change From Baseline in the EORTC Quality of Life Questionnaire - Neuroendocrine Carcinoid Module (EORTC QLQ-GINET21)
timeFrame: Inclusion (Baseline) (BL), Week 72, Week 120
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Cedars-Sinai Medical Center Samuel Oschin Cancer Center
state: California
city: Palo Alto
country: United States
facility: Stanford Cancer Center
state: California
city: Tampa
country: United States
facility: Moffitt Cancer Center
state: Florida
city: Chicago
country: United States
facility: Northwestern Medical Faculty Foundation
state: Illinois
city: Iowa City
country: United States
facility: University of Iowa Hospitals and Clinics
state: Iowa
city: Boston
country: United States
facility: Dana Farber Cancer Institute
state: Massachusetts
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Kettering
country: United States
facility: Kettering Medical Center
state: Ohio
city: Philadelphia
country: United States
facility: Perelman Center for Advanced Medicine
state: Pennsylvania
city: Nashville
country: United States
facility: Henry-Joyce Cancer Clinic
state: Tennessee
city: Houston
country: United States
facility: University of Texas MD Anderson Cancer Center
state: Texas
city: Houston
country: United States
facility: Excel Diagnostics and Nuclear Oncology Center
state: Texas
city: Leuven
country: Belgium
facility: Digestive Oncology, Leuven Cancer Institute
state: Brabant Flamand
city: Villejuif Cedex
country: France
facility: Institut Gustave Roussy
state: Ile De France
city: Toulouse
country: France
facility: Institut Claudius Regaud
state: Midi-Pyrénées
city: Nantes
country: France
facility: Hotel Dieu/CHU Nantes
state: Pays De La Loire
city: Marseille
country: France
facility: Hôpital la Timone /CHU Marseille
state: Provence-Alpes-Côte d'Azur
city: Lyon
country: France
facility: Centre Hospitalier Lyon-Sud
state: Rhône-Alpes
city: Clichy Cedex
country: France
facility: Hôpital Beaujon AP-HP
city: Munich
country: Germany
facility: Klinikum Rechts Isar, Nuclear Medicine
state: Bayern
city: Mainz
country: Germany
facility: Universitätsmedizin Mainz, Medizinische Klinik I Schwerpunkt Endokrinologie
state: Rheinland-Pfalz
city: Bad Berka
country: Germany
facility: Zentralklinik Bad Berka
state: Thüringen
city: Berlin
country: Germany
facility: Charité, Virchow-Klinikum, Gastroentrology, Hepatology & Endocrinology
city: Meldola
country: Italy
facility: Istituto Oncologico Romagnolo per lo Studio dei Tumori
state: Emilia-Romagna
city: Milano
country: Italy
facility: IEO Istituto Europeo di Oncologia
state: Lombardia
city: Macerata
country: Italy
facility: Presidio Osp. Di Macerata
state: Marche
city: Pisa
country: Italy
facility: Azienda Ospedaliero - Universitaria Pisana (Presidio Ospedaliero S. Chiara)
state: Toscana
city: Milano
country: Italy
facility: Fondazione IRCCS Istituto Nazionale dei Tumori
city: Roma
country: Italy
facility: Università "Sapienza" di Roma, Facoltà di Medicina e Psicologia, Ospedale S. Andrea-Roma
city: Coimbra
country: Portugal
facility: Centro Hospitalar e Universitario de Coimbra
state: Centro
city: Porto
country: Portugal
facility: Instituto Português de Oncologia
state: Norte
city: Hospitalet de Llobregat (Barcelona)
country: Spain
facility: University Hospital of Bellvitge
state: Cataluña
city: Madrid
country: Spain
facility: Ramon y Cajal University Hospital
city: Oxford
country: United Kingdom
facility: University of Oxford
state: South East England
city: Glasgow
country: United Kingdom
facility: Beatson Oncology Centre
city: London
country: United Kingdom
facility: Royal Free Hospital
city: London
country: United Kingdom
facility: Imperial College Healthcare Trust, Hammersmith Hospital
city: Manchester
country: United Kingdom
facility: The Christie NHS foundation Trust
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.