Study to Evaluate the Efficacy and Safety of Lutathera in Patients With Grade 2 and Grade 3 Advanced GEP-NET
- Conditions
- Gastro-enteropancreatic Neuroendocrine Tumor
- Interventions
- Drug: 30 mg Octreotide long acting repeatable (LAR) (Sandostatin LAR Depot)Drug: 2.5% Lys-Arg sterile amino acid solution
- Registration Number
- NCT03972488
- Lead Sponsor
- Advanced Accelerator Applications
- 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).
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- All
- Target Recruitment
- 226
- 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
- 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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- CROSSOVER
- Arm && Interventions
Group Intervention Description Optional post-progression re-treatment with Lutathera Lutathera Participants who received Lutathera in experimental arm and who progressed and met re-treatment eligibility criteria received additional 2 - 4 cycles of Lutathera (7.4 GBq/200 mCi x 4 cycles) Optional post-progression cross-over to Lutathera Lutathera Participants who received Octreotide LAR in Active comparator arm and who progressed and met cross-over eligibility criteria received maximum 4 cycles of Lutaathera (7.4 GBq/200 mCi x 4 cycles) plus octreotide long-acting (30 mg every 8 weeks). Lutathera® plus Octreotide LAR 30 mg (Investigational arm) 30 mg Octreotide long acting repeatable (LAR) (Sandostatin LAR Depot) Lutathera treatment consisted of a cumulative administered radioactivity of 29.6 GBq (800mCi) (7.4 GBq/200 mCi x 4 administrations every 8 +/- 1 week). Participants in the Lutathera arm were concomitantly administered with octreotide LAR 30 mg (Sandostatin LAR Depot) the day after each administration of Lutathera and no earlier than 4 hours after completion of the Lutathera infusion. Once Lutathera treatment completed, participants continued the 4-week interval administrations of 30 mg octreotide LAR until the completion of the Treatment Phase. Concomitantly with Lutathera, sterile amino acid solution was administered to minimize renal radiation exposure during Lutathera treatment. Lutathera® plus Octreotide LAR 30 mg (Investigational arm) Lutathera Lutathera treatment consisted of a cumulative administered radioactivity of 29.6 GBq (800mCi) (7.4 GBq/200 mCi x 4 administrations every 8 +/- 1 week). Participants in the Lutathera arm were concomitantly administered with octreotide LAR 30 mg (Sandostatin LAR Depot) the day after each administration of Lutathera and no earlier than 4 hours after completion of the Lutathera infusion. Once Lutathera treatment completed, participants continued the 4-week interval administrations of 30 mg octreotide LAR until the completion of the Treatment Phase. Concomitantly with Lutathera, sterile amino acid solution was administered to minimize renal radiation exposure during Lutathera treatment. Lutathera® plus Octreotide LAR 30 mg (Investigational arm) 2.5% Lys-Arg sterile amino acid solution Lutathera treatment consisted of a cumulative administered radioactivity of 29.6 GBq (800mCi) (7.4 GBq/200 mCi x 4 administrations every 8 +/- 1 week). Participants in the Lutathera arm were concomitantly administered with octreotide LAR 30 mg (Sandostatin LAR Depot) the day after each administration of Lutathera and no earlier than 4 hours after completion of the Lutathera infusion. Once Lutathera treatment completed, participants continued the 4-week interval administrations of 30 mg octreotide LAR until the completion of the Treatment Phase. Concomitantly with Lutathera, sterile amino acid solution was administered to minimize renal radiation exposure during Lutathera treatment. Octreotide LAR 60 mg (Control arm) High dose 60 mg octreotide long-acting repeatable Participants were administered with octreotide LAR 60 mg (Sandostatin LAR Depot) at 4-week intervals until the completion of the Treatment Phase. Optional post-progression re-treatment with Lutathera after cross-over Lutathera Participants who received Octreotide LAR in Active comparator arm subsequently entered cross-over, received Lutathera in cross-over, progressed for the second time and met re-treatment eligibility criteria could receive additional 2 - 4 cycles of Lutathera (7.4 GBq/200 mCi x 4 cycles). Optional post-progression re-treatment with Lutathera after cross-over High dose 60 mg octreotide long-acting repeatable Participants who received Octreotide LAR in Active comparator arm subsequently entered cross-over, received Lutathera in cross-over, progressed for the second time and met re-treatment eligibility criteria could receive additional 2 - 4 cycles of Lutathera (7.4 GBq/200 mCi x 4 cycles).
- Primary Outcome Measures
Name Time Method 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.
- Secondary Outcome Measures
Name Time Method Overall Response Rate (ORR) Per Central Assessment (Key Secondary) Up to approx. 42 months ORR is defined as the percentage of patients with the best overall response of complete response (CR) or partial response (PR) according to RECIST 1.1. CR = Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \< 10 mm; PR = At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters.
Time to Deteriration (TTD) Global Health Status, Diarrhea, Fatigue, Pain (EORTC QLQ-C30) (Key Secondary) Up to approx. 42 months TTD is defined as the first deterioration of at least 10 points from baseline in European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30): global health status, diarrhea, fatigue, and pain.
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).Disease Control Rate (DCR) Per Central Assessment Up to approx. 42 months Disease Control Rate is the percentage of participants with a best overall response of complete response (CR), partial response (PR) or stable disease (SD) (centrally assessed according to RECIST 1.1). CR = Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \< 10 mm; PR = At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters; SD = Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for progressive disease (PD).
Duration of Response (DOR) Per Central Assessment Up to approx. 42 months Duration of Response defined as time from first complete or partial response to progression or death due to underlying cancer according to RECIST 1.1.
Rate of Adverse Events from FPFV until end of study (about 94 months) Rate of adverse events scored according to CTCAE grade
Rate of Laboratory Toxicities from FPFV until end of study (about 94 months) Rate of laboratory toxicities scored according to CTCAE grade
Overall Survival (OS) from FPFV until end of study (about 94 months) OS is the time from randomization date until day of death due to any cause.
Trial Locations
- Locations (40)
Universitätsklinikum Essen - Klinik für Nuklearmedizin
🇩🇪Essen, Germany
Guys And St Thomas Hospital
🇬🇧London, United Kingdom
Bristol Haematology and Oncology Centre
🇬🇧Bristol, United Kingdom
Weston Park Hospital
🇬🇧Sheffield, United Kingdom
University of Iowa Hospitals and Clinics - Oncology
🇺🇸Iowa City, Iowa, United States
Mayo Clinic - Oncology
🇺🇸Rochester, Minnesota, United States
USF - H. Lee Moffitt Cancer Center and Research Institute
🇺🇸Tampa, Florida, United States
University of Kentucky UK Markey Cancer Center
🇺🇸Lexington, Kentucky, United States
London Health Sciences Centre, University of Western Ontario - Oncology
🇨🇦London, Canada
Sunnybrook Health Sciences Centre
🇨🇦Toronto, Canada
Hospices Civils de Lyon (HCL) - Hopital Edouard Herriot
🇫🇷Lyon, France
CHU Paris Nord-Val de Seine
🇫🇷Clichy, France
University of Genova - Oncology
🇮🇹Genova, Italy
CHU-Hôtel Dieu Service de Médecine Nucléaire
🇫🇷Nantes, France
A.O.di Bologna Policl.S.Orsola
🇮🇹Bologna, Italy
Institut Gustave Roussy
🇫🇷Villejuif, France
Universitätsklinikum Erlangen
🇩🇪Erlangen, Germany
Azienda Ospedaliera Sant'Andrea - Università La Sapienza U.O.C. Mal App. Digerente e - Oncology
🇮🇹Roma, Italy
Istituto Oncologico Romagnolo
🇮🇹Meldola, Italy
IRCCS fondazione Pascale - Oncology
🇮🇹Napoli, Italy
Fondazione Irccs Istituto Nazionale Tumori
🇮🇹Milano, Italy
Arcispedale Santa Maria Nuova, Reggio Emilia - Oncology
🇮🇹Reggio Emilia, Italy
Severance Hospital, Yonsei University Health System - Medical Oncology
🇰🇷Seoul, Korea, Republic of
UMC Utrecht - Oncology
🇳🇱Utrecht, Netherlands
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
Kings College Hospital - Oncology
🇬🇧London, United Kingdom
Royal Free Hospital, London
🇬🇧London, United Kingdom
Yale Cancer Center
🇺🇸New Haven, Connecticut, United States
Seoul National University Bundang Hospital
🇰🇷Seongnam-Si, Korea, Republic of
Centre Hospitalier Universitaire de Quebec
🇨🇦Quebec, Canada
BC Cancer Agency
🇨🇦Vancouver, Canada
Institut du Cancer de Montpellier - Oncology
🇫🇷Montpellier, France
Ieo, Irccs
🇮🇹Milano, Italy
Erasmus Medisch Centrum
🇳🇱Rotterdam, Netherlands
Asan Medical Center - Oncology
🇰🇷Seoul, Korea, Republic of
Seoul National University Hospital - Department of Internal Medicine
🇰🇷Seoul, Korea, Republic of
MD Anderson Cancer Center
🇺🇸Houston, Texas, United States