A Prospective Randomized Phase II Study Assess the Schema of Retreatment With Lutathera® ([177LU]LU-DOTA-TATE) in Patients With New Progression of Intestinal Well-differenciated Neuroendocrine Tumor
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 发起方
- 入组人数
- 146
- 试验地点
- 56
- 主要终点
- Evaluate the efficacy of two additional cycles of Lutathera® (one injection every two months), compared to active surveillance during 6 months in patients already retreated with two cycles.
研究概览
简要总结
In France, since the reimbursement of Lutathera®, this treatment is allowed for retreatment if patients still fulfill the criteria of its indication and 4 news cycles could be proposed. However, clinical practices are heterogeneous regarding the number of new cycles and most teams perform only two additional cycles (every 8 weeks). Therefore, the coordinator propose to evaluate the efficacy of two additional cycle of Lutathera® versus active surveillance in patients already retreated with two cycles Lutathera® for a new progression of intestinal neuroendocrine tumor and who previously received the 4 cycles of treatment with a clinical benefit.
详细描述
The NETTER-1 clinical trial compared peptide receptor radionuclide therapy (PRRT) with [177Lu]Lu-DOTA-TATE (Lutathera®) every eight weeks (4 doses) plus 30 mg octreotide LAR every 4 weeks with high dose (60 mg) of octreotide LAR every 4 weeks in patients with progressive and unresectable midgut neuroendocrine well differentiated (G1, G2) tumors (NETs) with somatostatin-receptor positive imaging (SSTRi+). Lutathera® improves both median progression free survival (PFS) (28.4 months vs 8.5 months) and median overall survival (OS) ("not reached" vs 27.4 months) with a follow-up of 42 months. Lutathera® also has an impact on quality of life. Therefore, this treatment was approved by the European Medicines Agency and is now reimbursed in France in that specific indication. Despite these promising results, progression will occur in most of patients within a variable time with limited treatment options left. Retreatment with additional cycles of Lutathera® may be an option. Van der Zwan et al. showed in a large retrospective cohort (the "ROTTERDAM cohort") a median PFS of 14.6 months after retreatment with two additional cycles of PRRT with [177Lu]Lu-DOTA-TATE and a significant longer OS than in the non-randomized control group. Interestingly, the safety was similar in salvage group than in initial PRRT: no grade (G) 3/4 renal toxicity occurred and hematological toxicities were similar to the group of patients who received the initial treatment (4 cycles). In a smaller cohort of 15 patients, Yordanova et al. showed that 8 or more cycles of [177Lu]Lu-DOTA-TATE were well tolerated and led to a survival improvement. In this study, each salvage therapy consisted of 2 or 3 cycles. No severe (G3, G4) renal toxicity or G4 adverse event occurred. In France, since the reimbursement of Lutathera®, this treatment is allowed for retreatment if patients still fulfill the criteria of its indication and 4 news cycles could be proposed. However, clinical practices are heterogeneous regarding the number of new cycles and most teams perform only two additional cycles (every 8 weeks). Therefore, the coordinator propose to evaluate the efficacy of two additional cycle of Lutathera® versus active surveillance in patients already retreated with two cycles Lutathera® for a new progression of intestinal neuroendocrine tumor and who previously received the 4 cycles of treatment with a clinical benefit.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 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
- •Age ≥ 18 years,
- •Histologically proven intestinal G1 or G2 neuroendocrine tumors (NET),
- •Patient previously treated with 4 cycles of Lutathera® (defined as "First PRRT"),
- •Disease control after "First PRRT" ≥ 12 months,
- •Patient presenting a progression of disease (clinic, biologic and/or radiologic) after a first PRRT,
- •Decision of retreatment with Lutathera® (defined as "Second PRRT") validated by RENATEN and/or multidisciplinary tumor board and in the scope of the French reimbursement process,
- •ECOG performance status 0-2,
- •Life expectancy ≥ 6 months as prognosticated by the physician,
- •Somatostatin receptor imaging positive imaging (SSTRi+) disease within 4 months prior to inclusion : (may be PET imaging (68Ga-based SSTR analogues) or scintigraphy imaging: 111In-pentetreotide or 99mTc-octreotide. At least 90% of lesions must be positive for SSTRi with a significant uptake (>= liver of surrounding tissue),
- •Measurable disease per RECIST 1.1 (Appendix 1), on CT/MRI scans, defined as at least 1 lesion with ≥ 1 cm in longest diameter, and ≥ 2 radiological tumors lesions in total,
- •Adequate bone marrow reserve (Hb > 8 g/dl, neutrophils ≥ 1500/mm³ and platelets ≥ 80 000/mm³),
- •Negative pregnancy test in women of childbearing potential (the β-HCG dosage must be ≤ 4 days before inclusion). Women who have no reproductive potential are postmenopausal women or women who have had permanent sterilization, eg. tubal occlusion, hysterectomy, bilateral salpingectomy),
- •Effective contraception in men or women of childbearing or pre-menopausal age and up to a minimum of 6 months following the end of treatment,
- •Patient´s signed written informed consent,
- •Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests and other study procedures,
- •Affiliation to the French Social Security System
排除标准
- •Patient who did not respond (no CR, PR or SD) to "first PRRT".
- •Radiological progression after two cycles of "Second PRRT" according to RECIST version 1.1,
- •Grade 4 hematotoxicity and/or nephrotoxicity during the initial PRRT, or unresolved AEs categorized as Grade 2 or higher (as per Common Terminology Criteria for Adverse Events (CTCAE v5.0) from previous PRRT cycles or any other therapy for NET, excluding alopecia and peripheral neuropathy,
- •Pancreatic NET,
- •NeuroEndocrine Carcinoma,
- •Prior external beam radiation therapy to more than 25% of the bone marrow,
- •Severe renal (estimated Glomerular Filtration Rate (GFR) according to Modification of Diet in Renal Disease (MDRD) < 40 mL/min or nephrotic syndrome) or hepatic insufficiency (Alanine aminotransferase (ALT)/ aspartate aminotransferase (AST) > 2.5 x ULN or ALT/AST > 5 x ULN if liver function abnormalities are due to the underlying malignancy and/or total serum bilirubin > 2.5 x ULN),
- •Serum albumin < 3.0 g/dL unless prothrombin time is within the normal range,
- •Uncontrolled diabetes mellitus as defined by a fasting blood glucose above 2 ULN,
- •Uncontrolled decompensated heart failure, myocardial infarction uncontrolled, stroke, pulmonary embolism or revascularization procedure, unstable angina pectoris, uncontrolled cardiac arrhythmia, and clinically significant bradycardia during the last 12 months,
- •Hypertension that cannot be controlled despite medications (≥ 160/95 mmHg despite optimal medical therapy)
- •Brain metastases (unless these metastases have been treated and stabilized for at least 24 weeks, prior to enrolment in the study. Patients with a history of brain metastases must have a head CT scan with contrast or MRI to document stable disease prior to enrolment in the study),
- •Pregnancy or breast feeding,
- •Substance abuse, medical, psychological, or social conditions that may interfere with the patient's participation in the study or evaluation of the study results,
- •Known hypersensitivity to any of the study drugs, study drug classes, or any constituent of the products,
- •Concomitant participation or participation within the last 30 days in another clinical trial,
- •History of other solid tumor in 5 years before the inclusion excepted of cancer in situ of the cervix and skin cancer (basal or squamous cell) treated and controlled.
- •Legal incapacity or physical, psychological or mental status interfering with the patient's ability to sign the informed consent or to terminate the study.
研究组 & 干预措施
Control arm
No treatment with active monitoring (clinical, biological and radiological follow-up) every 2 months.
Experimental arm
2 additional infusions of Lutathera® according to the marketing authorization schema
干预措施: Lutathera (Drug)
结局指标
主要结局
Evaluate the efficacy of two additional cycles of Lutathera® (one injection every two months), compared to active surveillance during 6 months in patients already retreated with two cycles.
时间窗: assessement every cycle (every 8 weeks) 6 months from randomization
defined as a change of tumoral assessment (Complete Response, Partial Response and Stable Disease from RECIST v1.1) with an evaluation every 2 months.
次要结局
- Evaluate the impact of two additional cycles of Lutathera® (one injection every two months), compared to active surveillance in term of Overall survival(the time without death during 5 years after the treatment)
- Evaluate the impact of two additional cycles of Lutathera® (one injection every two months), compared to active surveillance in term of Progression free survival(the time without progression of disease during 5 years after the treatment,)
- Evaluate the impact of two additional cycles of Lutathera® (one injection every two months), compared to active surveillance in term of Safety(during 6 months in patients already retreated with two cycles (each cycle is 8 weeks))
- To assess quality of life of general patient(during and after treatment in both arm : every 8 wweks during the treatment, every 3 months during 1 year post treatment and every year during 4 years post treatment)
- To assess quality of life of gastrointestinal neuroendocrine tumor(during and after treatment in both arm : every 8 wweks during the treatment, every 3 months during 1 year post treatment and every year during 4 years post treatment)