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
试验速览
- 阶段
- 3 期
- 状态
- 进行中（未招募）
- 入组人数
- 226
- 试验地点
- 40
- 主要终点
- Progression Free Survival (PFS) Per Central Assessment
研究概览
简要总结
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.
详细描述
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).
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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
研究组 & 干预措施
Lutathera® plus Octreotide LAR 30 mg (Investigational arm)
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.
干预措施: Lutathera (Drug)
Lutathera® plus Octreotide LAR 30 mg (Investigational arm)
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.
干预措施: 30 mg Octreotide long acting repeatable (LAR) (Sandostatin LAR Depot) (Drug)
Lutathera® plus Octreotide LAR 30 mg (Investigational arm)
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.
干预措施: 2.5% Lys-Arg sterile amino acid solution (Drug)
Octreotide LAR 60 mg (Control arm)
Participants were administered with octreotide LAR 60 mg (Sandostatin LAR Depot) at 4-week intervals until the completion of the Treatment Phase.
干预措施: High dose 60 mg octreotide long-acting repeatable (Drug)
Optional post-progression re-treatment with 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)
干预措施: Lutathera (Drug)
Optional post-progression cross-over to 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).
干预措施: Lutathera (Drug)
Optional post-progression re-treatment with Lutathera after cross-over
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).
干预措施: Lutathera (Drug)
Optional post-progression re-treatment with Lutathera after cross-over
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).
干预措施: High dose 60 mg octreotide long-acting repeatable (Drug)
结局指标
主要结局
Progression Free Survival (PFS) Per Central Assessment
时间窗: 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.
次要结局
- Overall Response Rate (ORR) Per Central Assessment (Key Secondary)(Up to approx. 42 months)
- Time to Deteriration (TTD) Global Health Status, Diarrhea, Fatigue, Pain (EORTC QLQ-C30) (Key Secondary)(Up to approx. 42 months)
- Disease Control Rate (DCR) Per Central Assessment(Up to approx. 42 months)
- Duration of Response (DOR) Per Central Assessment(Up to approx. 42 months)
- Rate of Adverse Events(from FPFV until end of study (about 94 months))
- Rate of Laboratory Toxicities(from FPFV until end of study (about 94 months))
- Overall Survival (OS)(from FPFV until end of study (about 94 months))