Randomized Open Label Study to Compare the Efficacy and Safety of Everolimus Followed by Chemotherapy With Streptozotocin- Fluorouracilo (STZ-5FU) Upon Progression or the Reverse Sequence, in Advanced Progressive Pancreatic NETs (pNETs)
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 发起方
- 入组人数
- 141
- 试验地点
- 37
- 主要终点
- First Progression Free Survival (PFS1)
研究概览
简要总结
The purpose of this study is to compare streptozotocin (STZ) vs everolimus as first line treatment for advanced pNET and to elucidate which sequence of STZ based chemotherapy and the mammalian Target of Rapamycin (mTOR) inhibitor, everolimus, gives better results in terms of second Progression Free Survival (PFS) in well differentiated and advanced pancreatic NETs.
详细描述
STZ plus 5-Fuorouracil (5FU) is the actual standard of care for advanced pancreatic Neuroendocrine tumours (pNETS) in the European Union. Everolimus has been recently approved for its use in advanced pNETs by the Food and Drug Administration (FDA) and in Europe by the European Medical Agency (EMA).
A randomized study is needed to have a clear knowledge about the best sequence for its administration; this is, before or after palliative chemotherapy.
There may or may not be any benefits from giving first each other treatment of the study. The information obtained from this study will help the physician improve the treatment and management of patients with advanced pNET.
This study was planned to compare STZ-5FU chemotherapy followed by everolimus upon progression versus the reverse sequence. However sequential studies with pNETs are hard to be managed in terms of time and costs. Therefore the protocol was amended to have PFS1 (progression free survival after course 1) as primary endpoint and PFS2 (i.e. progression free survival after both STZ based chemotherapy and Everolimus or the reverse order) as secondary endpoint. This information will be extremely valuable for the day to day clinical practice of pNETs oncologists
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 94 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Histologically proven diagnosis of unresectable or metastatic, advanced pancreatic NET.
- •Documented confirmation of pancreatic NET G1 or G2 as per European Neuroendocrine Society (ENETS) classification system.
- •Patients from whom a paraffin-embedded primary tumour or metastasis block is available and to be sent by Courier.
- •Before study inclusion, patients must show progressive disease documented by radiology 12 months prior to study inclusion. Treatment naive patients can be also included if the patient needs active treatment with either chemotherapy or everolimus.
- •Presence of measurable disease as per Response Evaluation Criteria in Solid Tumors (RECIST) criteria 1.0, documented by a Triphasic Computed Tomography (CT) scan or multiphase MRI radiological assessment.
- •Previous treatment with somatostatin (SS) analogues is allowed. Only those patients with active functioning syndrome at entry can continue with SS analogues during the study.
- •Adequate bone marrow and renal functions, and serum fasting cholesterol
- •Women with child-bearing potential must have a negative serum pregnancy test.
- •Written Informed Consent obtained according to local regulations
排除标准
- •Previous treatment with chemotherapy and/or mTOR inhibitors or tyrosine kinase inhibitors.
- •Immune therapy or radiation therapy within 4 weeks prior to the patient entering the study.
- •Hepatic artery embolization within the last 6 months (1 month if there are other sites of measurable disease), or cryoablation/radiofrequency ablation of hepatic metastasis within 2 months of enrolment.
- •Previous treatment with Peptide-Receptor Radionuclide Therapy (PRRT) within the last 6 months and/or without progression following PRRT.
- •Uncontrolled diabetes mellitus.
- •Any severe and/or uncontrolled medical conditions.
- •Treatment with potent inhibitors or inducers of Cytochrome P450 3A4 (CYP3A) isoenzyme within 5 days immediately before the start of treatment.
- •Patients on chronic treatment with corticosteroids or any other immunosuppressive agent.
- •Patients known to be HIV seropositive.
- •Known intolerance or hypersensitivity to everolimus or its excipients or other rapamycin analogues. Patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
- •Known intolerance or hypersensitivity to 5FU or STZ or its excipients (notice that this criterion includes patients with known deficit of dihydropyrimidine dehydrogenase deficiency -DPD).
- •Pregnant, lactating women or fertile adults not using effective birth control methods.
- •For administrative matters (insurance) patients ≥ 95 are not allowed during the trial.
- •Only those patients coming from the hospital pool will be included in SEQTOR trial (e.g. persons detained in an institution as a result of an official or court order are excluded).
研究组 & 干预措施
Sequence A, drug: everolimus first
Everolimus (10mg/daily, oral) followed by STZ-5FU (injection/infusion; Moertel or Uppsala regime).
干预措施: STZ-5FU (Drug)
Sequence B, drug: STZ - 5FU first
STZ-5FU (injection/infusion; Moertel or Uppsala regime) followed by Everolimus (10 mg/ daily, oral)
干预措施: STZ-5FU (Drug)
结局指标
主要结局
First Progression Free Survival (PFS1)
时间窗: At 12 months
Proportion of patients who are alive without progression to Course 1 from the date of randomization in STZ based CT vs Everolimus arms Definitions for PFS rate for course 1 at 12 months: * No: number (proportion) of patients who were not alive and progression free according to the respective definition (main, conservative, and optimistic); * Yes: number (proportion) of patients who were alive and progression free according to the respective definition (main, conservative, and optimistic).
次要结局
- Second Progression Free Survival (Second PFS)(Until the end of study every 12 weeks, approximately up to 5 years)
- Progression-free Survival (PFS) to First Treatment(Throughout the study period every 12 weeks, approximately up to 5 years)
- Adverse Events (AEs) Rate(Throughout the study period in continous monitoring at every visit for approximately up to 5 years)
- Frequency of Dose Modifications to First Treatment(Throughout the study period, approximately up to 5 years)
- Best Overall Response (BOR) to First Study Treatment(Throughout the study period, every 12 weeks up to approximately 5 years)
- Objective Response Rate (ORR) to First Study Treatment(Throughout the study period every 12 weeks, up to approximately 5 years)
- Frequency of Dose Modifications to Second Treatment(Throughout the study period, approximately up to 5 years)
- Overall Survival (OS)(Throughout the study period, up to approximately 5 years)
- Best Overall Response (BOR) to Second Study Treatment(Throughout the study period, every 12 weeks up to approximately 5 years)
- Objective Response Rate (ORR) to Second Study Treatment(Throughout the study period every 12 weeks, up to approximately 5 years)
- Progression-free Survival (PFS) to Second Treatment(Throughout the study period every 12 weeks, approximately up to 2 years)