Active, not recruiting
Phase 3
Study to Evaluate the Efficacy and Safety of Lutathera in Patients With Grade 2 and Grade 3 Advanced GEP-NET
Condition(s) studied
Gastro-enteropancreatic Neuroendocrine Tumor
Investigational drug(s) / intervention(s)
Lutathera30 mg Octreotide long acting repeatable (LAR) (Sandostatin LAR Depot)2.5% Lys-Arg sterile amino acid solutionHigh dose 60 mg octreotide long-acting repeatable
Lutathera: Lutathera is a sterile radiopharmaceutical supplied as a ready-to-use solution for infusion containing 177Lu-DOTA0-Tyr3-octreotate as a drug substance with a volumetric activity of 370 MBq/mL at reference date and time (calibration time). Each Lutathera infusion continued for 30 min.
30 mg Octreotide long acting repeatable (LAR) (Sandostatin LAR Depot): Sandostatin® LAR Depot (octreotide LAR) is a pharmaceutical that was available in single-use kits containing a 6-mL vial of 10 mg, 20 mg, or 30 mg strength for intramuscular injection, a syringe containing 2.5 mL of diluent, two sterile 1½" 19-gauge needles, and two alcohol wipes.
2.5% Lys-Arg sterile amino acid solution: Participants who received Lutathera were administered a concomitant 2.5% Lys-Arg solution for kidney protection, with each Lutathera dose. The 2.5% Lys-Arg solution was administered intravenously for 4 hours (infusion rate: 250 ml/h); the infusion was to start 30 minutes prior to the start of the Lutathera infusion and continue during (30 min) and up to at least 3 hours after the Lutathera infusion.
High dose 60 mg octreotide long-acting repeatable: Sandostatin® LAR Depot (octreotide LAR) is a pharmaceutical that was available in single-use kits containing a 6-mL vial of 10 mg, 20 mg, or 30 mg strength for intramuscular injection, a syringe containing 2.5 mL of diluent, two sterile 1½" 19-gauge needles, and two alcohol wipes.
Study summary
The aim of NETTER-2 was to determine if Lutathera in combination with long-acting octreotide prolongs progression free survival (PFS) in gastroenteropancreatic neuroendocrine tumor (GEP-NET) patients with high proliferation rate tumors (G2 and G3), when given as a first line treatment compared to treatment with high dose (60 mg) long-acting octreotide. Somatostatin analog (SSA) naive patients were eligible, as well as patients previously treated with SSAs in the absence of progression.
Eligibility
Inclusion Criteria:
* Presence of metastasized or locally advanced, inoperable (curative intent) histologically proven, well differentiated Grade 2 or Grade 3 gastroenteropancreatic neuroendocrine (GEP-NET) tumor diagnosed within 6 months prior to screening.
* Ki67 index ≥10 and ≤ 55%
* Patients ≥ 15 years of age and a body weight of \> 40 kg at screening
* Expression of somatostatin receptors on all target lesions documented by CT/MRI scans, assessed by any of the following somatostatin receptor imaging (SRI) modalities within 3 months prior to randomization: \[68Ga\]-DOTA-TOC (e.g. Somakit-TOC®) PET/CT (or MRI when applicable based on target lesions) imaging, \[68Ga\]-DOTA-TATE PET/CT (or MRI when applicable based on target lesions) imaging (e.g. NETSPOT®), Somatostatin Receptor scintigraphy (SRS) with \[111In\]-pentetreotide (Octreoscan® SPECT/CT), SRS with \[99mTc\]-Tektrotyd, \[64Cu\]-DOTA-TATE PET/CT (or MRI when applicable based on target lesions) imaging.
* The tumor uptake observed in the target lesions must be \> normal liver uptake.
* Karnofsky Performance Score (KPS) ≥ 60
* Presence of at least 1 measurable site of disease
* Patients who have provided a signed informed consent form to participate in the study, obtained prior to the start of any protocol related activities
Exclusion Criteria:
* Creatinine clearance \< 40 mL/min calculated by the Cockroft Gault method
* Hb concentration \< 5.0 mmol/L (\<8.0 g/dL); WBC \< 2x10E9/L (2000/mm3); platelets \< 75x10E9/L (75x10E3/mm3)
* Total bilirubin \> 3 x ULN
* Serum albumin \< 3.0 g/dL unless prothrombin time is within the normal range
* Pregnancy or lactation
* Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, are not allowed to participate in this study UNLESS they are using highly effective methods of contraception throughout the study treatment period (including cross-over and re-treatment, if applicable) and for 7 months after study drug discontinuation
* Peptide receptor radionuclide therapy (PRRT) at any time prior to randomization in the study.
* Documented RECIST progression to previous treatments for the current GEP-NET at any time prior to randomization
* Patients for whom in the opinion of the investigator other therapeutic options (eg chemo-, targeted therapy) are considered more appropriate than therapy offered in the study, based on patient and disease characteristics
* Any previous therapy with Interferons, Everolimus (mTOR-inhibitors), chemotherapy or other systemic therapies for GEP-NET administered for more than 1 month or within 12 weeks prior to randomization in the study.
* Any previous radioembolization, chemoembolization and radiofrequency ablation for GEP-NET
* Any surgery within 12 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 screening in the study. Patients with a history of brain metastases must have a head CT or MRI with contrast to document stable disease prior to randomization in the study.
* Uncontrolled congestive heart failure (NYHA II, III, IV). Patients with history of congestive heart failure who do not violate this exclusion criterion will undergo an evaluation of their cardiac ejection fraction prior to randomization via echocardiography. The results from an earlier assessment (not exceeding 30 days prior to randomization) may substitute the evaluation at the discretion of the Investigator, if no clinical worsening is noted. The patient's measured cardiac ejection fraction in these patients must be ≥40% before randomization.
* QTcF \> 470 msec for females and QTcF \> 450 msec for males or congenital long QT syndrome
* Uncontrolled diabetes mellitus as defined by hemoglobin A1c value \> 7.5%
* Hyperkaleamia \> 6.0 mmol/L (CTCAE Grade 3) which is not corrected prior to study enrolment
* Any patient receiving treatment with short-acting octreotide, which cannot be interrupted for 24 h before and 24 h after the administration of Lutathera, or any patient receiving treatment with SSAs (e.g. octreotide long-acting), which cannot be interrupted for at least 6 weeks before the administration of Lutathera.
* 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
* Patient with known incompatibility to CT Scans with IV contrast due to allergic reaction or renal insufficiency. If such a patient can be imaged with MRI, then the patient would not be excluded.
* Hypersensitivity to any somatostatin analogues, the IMPs active substance or to any of the excipients.
* Patients who have participated in any therapeutic clinical study/received any investigational agent within the last 30 days
Primary outcome measure(s)
- Progression Free Survival (PFS) Per Central Assessment — from randomization to the first line progression or death due to any cause, up to approx. 42 months
PFS is the time from randomization to the first line progression (centrally assessed according to RECIST 1.1) or death due to any cause. Progression is defined using Response Evaluation Criteria in Solid Tumor Criteria (RECIST 1.1) as a 20% increase in the sum of diameters of all measured target lesions or unequivocal progression of non-target lesions or appearance of a new lesion.
Trial sites (40)
| Facility | City | Region | Status |
| Yale Cancer Center |
New Haven |
Connecticut |
|
| USF - H. Lee Moffitt Cancer Center and Research Institute |
Tampa |
Florida |
|
| University of Iowa Hospitals and Clinics - Oncology |
Iowa City |
Iowa |
|
| University of Kentucky UK Markey Cancer Center |
Lexington |
Kentucky |
|
| Mayo Clinic - Oncology |
Rochester |
Minnesota |
|
| MD Anderson Cancer Center |
Houston |
Texas |
|
| London Health Sciences Centre, University of Western Ontario - Oncology |
London |
Canada |
|
| Centre Hospitalier Universitaire de Quebec |
Québec |
Canada |
|
| Sunnybrook Health Sciences Centre |
Toronto |
Canada |
|
| BC Cancer Agency |
Vancouver |
Canada |
|
| CHU Paris Nord-Val de Seine |
Clichy |
France |
|
| Hospices Civils de Lyon (HCL) - Hopital Edouard Herriot |
Lyon |
France |
|
| Institut du Cancer de Montpellier - Oncology |
Montpellier |
France |
|
| CHU-Hôtel Dieu Service de Médecine Nucléaire |
Nantes |
France |
|
| Institut Gustave Roussy |
Villejuif |
France |
|
| Universitätsklinikum Erlangen |
Erlangen |
Germany |
|
| Universitätsklinikum Essen - Klinik für Nuklearmedizin |
Essen |
Germany |
|
| A.O.di Bologna Policl.S.Orsola |
Bologna |
Italy |
|
| University of Genova - Oncology |
Genova |
Italy |
|
| Istituto Oncologico Romagnolo |
Meldola |
Italy |
|
| Fondazione Irccs Istituto Nazionale Tumori |
Milan |
Italy |
|
| Ieo, Irccs |
Milan |
Italy |
|
| IRCCS fondazione Pascale - Oncology |
Naples |
Italy |
|
| Arcispedale Santa Maria Nuova, Reggio Emilia - Oncology |
Reggio Emilia |
Italy |
|
| Azienda Ospedaliera Sant'Andrea - Università La Sapienza U.O.C. Mal App. Digerente e - Oncology |
Roma |
Italy |
|
| Erasmus Medisch Centrum |
Rotterdam |
Netherlands |
|
| UMC Utrecht - Oncology |
Utrecht |
Netherlands |
|
| Seoul National University Bundang Hospital |
Seongnam-si |
South Korea |
|
| Asan Medical Center - Oncology |
Seoul |
South Korea |
|
| Seoul National University Hospital - Department of Internal Medicine |
Seoul |
South Korea |
|
| Severance Hospital, Yonsei University Health System - Medical Oncology |
Seoul |
South Korea |
|
| Hospital Universitario Vall d'Hebrón |
Barcelona |
Spain |
|
| Hospital General Universitario Gregorio Marañón |
Madrid |
Spain |
|
| Hospital Universitario Ramón y Cajal |
Madrid |
Spain |
|
| Hospital Universitari i Politecnic La Fe |
Valencia |
Spain |
|
| Bristol Haematology and Oncology Centre |
Bristol |
United Kingdom |
|
| Guys And St Thomas Hospital |
London |
United Kingdom |
|
| Kings College Hospital - Oncology |
London |
United Kingdom |
|
| Royal Free Hospital, London |
London |
United Kingdom |
|
| Weston Park Hospital |
Sheffield |
United Kingdom |
|
More Advanced Accelerator Applications trials in the UK