Clinical trial NCT03972488: Study to Evaluate the Efficacy and Safety of Lutathera in Patients With Grade 2 and Grade 3 Advanced GEP-NET
Official title: A Phase III Multi-center, Randomized, Open-label Study to Evaluate the Efficacy and Safety of Lutathera in Patients With Grade 2 and Grade 3 Advanced GEP-NET
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Gastro-enteropancreatic Neuroendocrine Tumor
Keywords: Lutathera
GEP-NET
NETTER-2
177Lu-DOTA0-TATE
Lutetium oxodotreotide
Lutetium dotatate
AAA601
Lead sponsor: Advanced Accelerator Applications
Sponsor class: INDUSTRY
First posted: 2019-06-03
Enrollment: 226
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief 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.

Detailed description: The study consisted of a screening phase, a treatment phase, an optional cross-over phase for subjects assigned to the control arm, optional re-treatment phase for subjects assigned to the Lutathera arm, and a follow-up phase. This study compared treatment with Lutathera (7.4 GBq/200 mCi 4 × administrations every 8 weeks ± 1 week; cumulative dose: 29.6 GBq/800mCi) plus octreotide long-acting release (LAR) (30 mg every 8 weeks during Lutathera treatment and every 4 weeks after last Lutathera treatment) and high dose octreotide LAR (60 mg every 4 weeks).

Eligibility criteria: 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 outcomes:
measure: Progression Free Survival (PFS) Per Central Assessment
timeFrame: from randomization to the first line progression or death due to any cause, up to approx. 42 months
Secondary outcomes:
measure: Overall Response Rate (ORR) Per Central Assessment (Key Secondary)
timeFrame: Up to approx. 42 months
measure: Time to Deteriration (TTD) Global Health Status, Diarrhea, Fatigue, Pain (EORTC QLQ-C30) (Key Secondary)
timeFrame: Up to approx. 42 months
measure: Disease Control Rate (DCR) Per Central Assessment
timeFrame: Up to approx. 42 months
measure: Duration of Response (DOR) Per Central Assessment
timeFrame: Up to approx. 42 months
measure: Rate of Adverse Events
timeFrame: from FPFV until end of study (about 94 months)
measure: Rate of Laboratory Toxicities
timeFrame: from FPFV until end of study (about 94 months)
measure: Overall Survival (OS)
timeFrame: from FPFV until end of study (about 94 months)
Other outcomes:
Locations:
city: New Haven
country: United States
facility: Yale Cancer Center
state: Connecticut
city: Tampa
country: United States
facility: USF - H. Lee Moffitt Cancer Center and Research Institute
state: Florida
city: Iowa City
country: United States
facility: University of Iowa Hospitals and Clinics - Oncology
state: Iowa
city: Lexington
country: United States
facility: University of Kentucky UK Markey Cancer Center
state: Kentucky
city: Rochester
country: United States
facility: Mayo Clinic - Oncology
state: Minnesota
city: Houston
country: United States
facility: MD Anderson Cancer Center
state: Texas
city: London
country: Canada
facility: London Health Sciences Centre, University of Western Ontario - Oncology
city: Quebec
country: Canada
facility: Centre Hospitalier Universitaire de Quebec
city: Toronto
country: Canada
facility: Sunnybrook Health Sciences Centre
city: Vancouver
country: Canada
facility: BC Cancer Agency
city: Clichy
country: France
facility: CHU Paris Nord-Val de Seine
city: Lyon
country: France
facility: Hospices Civils de Lyon (HCL) - Hopital Edouard Herriot
city: Montpellier
country: France
facility: Institut du Cancer de Montpellier - Oncology
city: Nantes
country: France
facility: CHU-Hôtel Dieu Service de Médecine Nucléaire
city: Villejuif
country: France
facility: Institut Gustave Roussy
city: Erlangen
country: Germany
facility: Universitätsklinikum Erlangen
city: Essen
country: Germany
facility: Universitätsklinikum Essen - Klinik für Nuklearmedizin
city: Bologna
country: Italy
facility: A.O.di Bologna Policl.S.Orsola
city: Genova
country: Italy
facility: University of Genova - Oncology
city: Meldola
country: Italy
facility: Istituto Oncologico Romagnolo
city: Milano
country: Italy
facility: Fondazione Irccs Istituto Nazionale Tumori
city: Milano
country: Italy
facility: Ieo, Irccs
city: Napoli
country: Italy
facility: IRCCS fondazione Pascale - Oncology
city: Reggio Emilia
country: Italy
facility: Arcispedale Santa Maria Nuova, Reggio Emilia - Oncology
city: Roma
country: Italy
facility: Azienda Ospedaliera Sant'Andrea - Università La Sapienza U.O.C. Mal App. Digerente e - Oncology
city: Seongnam-Si
country: Korea, Republic of
facility: Seoul National University Bundang Hospital
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center - Oncology
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital - Department of Internal Medicine
city: Seoul
country: Korea, Republic of
facility: Severance Hospital, Yonsei University Health System - Medical Oncology
city: Rotterdam
country: Netherlands
facility: Erasmus Medisch Centrum
city: Utrecht
country: Netherlands
facility: UMC Utrecht - Oncology
city: Barcelona
country: Spain
facility: Hospital Universitario Vall d'Hebrón
city: Madrid
country: Spain
facility: Hospital General Universitario Gregorio Marañón
city: Madrid
country: Spain
facility: Hospital Universitario Ramón y Cajal
city: Valencia
country: Spain
facility: Hospital Universitari i Politecnic La Fe
city: Bristol
country: United Kingdom
facility: Bristol Haematology and Oncology Centre
city: London
country: United Kingdom
facility: Guys And St Thomas Hospital
city: London
country: United Kingdom
facility: Kings College Hospital - Oncology
city: London
country: United Kingdom
facility: Royal Free Hospital, London
city: Sheffield
country: United Kingdom
facility: Weston Park Hospital
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References:
citation: Singh S, Halperin D, Myrehaug S, Herrmann K, Pavel M, Kunz PL, Chasen B, Tafuto S, Lastoria S, Capdevila J, Garcia-Burillo A, Oh DY, Yoo C, Halfdanarson TR, Falk S, Folitar I, Zhang Y, Aimone P, de Herder WW, Ferone D; all the NETTER-2 Trial Investigators. [177Lu]Lu-DOTA-TATE plus long-acting octreotide versus high-dose long-acting octreotide for the treatment of newly diagnosed, advanced grade 2-3, well-differentiated, gastroenteropancreatic neuroendocrine tumours (NETTER-2): an open-label, randomised, phase 3 study. Lancet. 2024 Jun 29;403(10446):2807-2817. doi: 10.1016/S0140-6736(24)00701-3. Epub 2024 Jun 5.
citation: Jungels C, Deleporte A. State of the art and future directions in the systemic treatment of neuroendocrine neoplasms. Curr Opin Oncol. 2021 Jul 1;33(4):378-385. doi: 10.1097/CCO.0000000000000740.