MGMT-NET: O6-methylguanine-DNA Methyltransferase (MGMT) Status in Neuroendocrine Tumors: Predictive Factor of Response to Alkylating Agents
试验速览
- 阶段
- 不适用
- 状态
- 已完成
- 入组人数
- 116
- 试验地点
- 19
- 主要终点
- Objective Response (OR) in patients treated with alkylating-based chemotherapy
研究概览
简要总结
Neuroendocrine tumors (NET) are rare but their incidence is growing. Alkylating agents (ALKY) are one of the main systemic treatments used, at least for advanced duodeno-pancreatic NETs, with a response rate of 30 to 40% and a median progression-free survival of 4 to 18 months. Chemotherapy is one of the few therapeutic weapons, along with everolimus, somatostatin analogs, and metabolic radiotherapy, for lung NETs, called typical and atypical carcinoids, even if the level of proof of efficacy for these treatments is lower than for duodeno-pancreatic NETs. Considering the available retrospective data, O6-Methylguanine-DNA methyltransferase (MGMT) appears to be a predictive factor of the response to ALKY. Oxaliplatin (OX) has demonstrated an interesting activity, with response rates between 17% and 30%. In a first retrospective study we showed that Gemox is effective in NET, and more recently that its activity is similar to that of ALKYs, but without being influenced by the MGMT status. Prospective studies are needed but our data suggests that ALKY should be offered first to patients with methylated MGMT tumors while Oxaliplatin-based chemotherapy should be offered first to patients with unmethylated MGMT tumors.
In this project, we wish to evaluate the contribution of the MGMT methylation, evaluated in the tumor, in predicting the Objective Response (OR) in patients treated with ALKY and to evaluate a treatment with alkylating agents versus Oxaliplatin in patients with a duodeno-pancreatic or lung or unknown primitive NET.
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 greater than or equal to 18 years;
- •Patient presenting well-differentiated advanced grade 1-3 (locally/metastatic) duodeno-pancreatic or thoracic (lung or thymus) or unknown primitive NETs, not curable with surgery.
- •Patients must have measurable disease using the RECIST v1.1 criteria;
- •Indication for cytotoxic systemic chemotherapy validated by the dedicated Multidisciplinary Tumor Board;
- •MRI or TAP CT scan with contrast agents within 4 weeks +/- 1 week before beginning of treatment;
- •Tumor tissue available (fresh frozen or paraffin-embedded) in order to search for the methyl guanine methyltransferase (MGMT) status;
- •Patients with childbearing potential should use effective contraception during the study and the following 6 months;
- •Covered by a Healthcare System where applicable, and/or in compliance with the recommendations of the national laws in force relating to biomedical research;
- •Subject able to understand and willing to sign a written informed consent document;
- •Signed written informed consent obtained prior to any study-specific screening procedures.
- •Previous treatments such as surgery, radiofrequency ablation, transarterial liver embolization, somatostatin analogs, interferon, everolimus or other targeted therapy, peptide receptor radionuclide treatment (PRRT) and chemotherapy (platin-etoposide, folfiri, paclitaxel or docetaxel) are allowed.
排除标准
- •Previous chemotherapy using Oxaliplatin or ALKY (streptozotocin, dacarbazin or temozolomide). Other chemotherapy (platin-etoposide, folfiri, paclitaxel or docetaxel) are allowed;
- •Pregnant or breastfeeding;
- •Men and women of childbearing age potential not using medically accepted contraceptive measures, as judged by the investigator;
- •Contraindication to any drug contained in the chemotherapy regimen;
- •Any significant disease which, in the investigator's opinion, excludes the patient from the study;
- •Under any administrative or legal supervision.
研究组 & 干预措施
Unmethylated MGMT NET - OX
Patients with unmethylated MGMT NET will be randomly assigned (1:1) to either the alkylating-based chemotherapy arm or to the oxaliplatin-based chemotherapy arm.
The "oxaliplatin-based" group will receive gemox (gemcitabine-oxaliplatin, 1x/2 week); alternatively folfox (5 fluorouracil-leucovorin-oxaliplatin, 1x/2 week) or capox (capecitabine-oxaliplatin, 1x/3 week).
干预措施: Oxaliplatin-based chemotherapy (Drug)
Unmethylated MGMT NET - ALKY
Patients with unmethylated MGMT NET will be randomly assigned (1:1) to either the alkylating-based chemotherapy arm or to the oxaliplatin-based chemotherapy arm.
The "alkylating-based" group will receive CapTem regimen (capecitabine and temozolomide, /4 week), alternatively LV5FU2 (folinic acid-5 fluorouracil)-dacarbazine (1x/2 week) or LV5FU2 (folinic acid-5-fluorouracil)-streptozotocine (1x/2 week).
干预措施: Alkylating-based chemotherapy (Drug)
Methylated MGMT NET - OX
Patients with methylated MGMT NET will be randomly assigned (2:1) to either the alkylating-based chemotherapy arm or to the oxaliplatin-based chemotherapy arm.
The "oxaliplatin-based" group will receive gemox (gemcitabine-oxaliplatin, 1x/2 week); alternatively folfox (5 fluorouracil-leucovorin-oxaliplatin, 1x/2 week) or capox (capecitabine-oxaliplatin, 1x/3 week).
干预措施: Oxaliplatin-based chemotherapy (Drug)
Methylated MGMT NET - ALKY
Patients with methylated MGMT NET will be randomly assigned (2:1) to either the alkylating-based chemotherapy arm or to the oxaliplatin-based chemotherapy arm.
The "alkylating-based" group will receive CapTem regimen (capecitabine and temozolomide, /4 week), alternatively LV5FU2 (folinic acid-5 fluorouracil)-dacarbazine (1x/2 week) or LV5FU2 (folinic acid-5-fluorouracil)-streptozotocine (1x/2 week).
干预措施: Alkylating-based chemotherapy (Drug)
结局指标
主要结局
Objective Response (OR) in patients treated with alkylating-based chemotherapy
时间窗: 3 months
Objective Response (OR) in NETs patients treated with alkylating-based chemotherapy according to O6-Methyl guanine methyltransferase (MGMT) methylation status. The evaluation of OR is evaluation of complete response (CR) or partial response (PR) assessed by CT scan TAP or MRI with injection using the RECIST v1.1 criteria by centralized reading carried out by an expert radiologist blinded to the results of the MGMT methylation (methylated or un-methylated).
次要结局
- Objective Response (OR) assessed by immunochemistry on tissue(3 months)
- Progression Free Survival (PFS) in patients treated with alkylating-based chemotherapy(3 months)
- Progression Free Survival (PFS) in patients treated with oxaliplatin-based chemotherapy(3 months)
- Overall Survival (OS) in patients treated with alkylating-based chemotherapy(3 months)
- Overall Survival (OS) in patients treated with oxaliplatin-based chemotherapy(3 months)
- Objective Response (OR) in patients treated with oxaliplatin-based chemotherapy(3 months)