MGMT-NET: O6-methylguanine-DNA Methyltransferase (MGMT) Status in Neuroendocrine Tumors: Predictive Factor of Response to Alkylating Agents
- Conditions
- Neuroendocrine Tumors
- Interventions
- Drug: Alkylating-based chemotherapyDrug: Oxaliplatin-based chemotherapy
- Registration Number
- NCT03217097
- Lead Sponsor
- Hospices Civils de Lyon
- Brief Summary
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.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 116
- 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.
- 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.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Methylated MGMT NET - ALKY Alkylating-based chemotherapy 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). Unmethylated MGMT NET - ALKY Alkylating-based chemotherapy 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). Unmethylated MGMT NET - OX Oxaliplatin-based chemotherapy 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). Methylated MGMT NET - OX Oxaliplatin-based chemotherapy 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).
- Primary Outcome Measures
Name Time Method Objective Response (OR) in patients treated with alkylating-based chemotherapy 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).
- Secondary Outcome Measures
Name Time Method Objective Response (OR) assessed by immunochemistry on tissue 3 months Objective Response (OR) at 3 months assessed by RECIST v1.1 criteria in patients with unmethylated MGMT NETs and in patients with methylated MGMT NETs evaluated with immunochemistry (IHC) on tissue
Progression Free Survival (PFS) in patients treated with alkylating-based chemotherapy 3 months Progression Free Survival (PFS) in patients treated with alkylating-based chemotherapy according to MGMT methylation status. Progression Free Survival (PFS) is defined as the time from random assignment in a clinical trial to disease progression (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) or death from any cause.
Progression Free Survival (PFS) in patients treated with oxaliplatin-based chemotherapy 3 months Progression Free Survival (PFS) in patients treated with oxaliplatin-based chemotherapy according to MGMT methylation status. Progression Free Survival (PFS) is defined as the time from random assignment in a clinical trial to disease progression (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) or death from any cause.
Overall Survival (OS) in patients treated with alkylating-based chemotherapy 3 months Overall Survival (OS) in patients treated with alkylating-based chemotherapy according to MGMT methylation status. Overall Survival (OS) is defined as the time from random assignment to the date of death due to any cause, or to the date of censoring at the last time the subject was known to be alive in intention-to-treat populations
Overall Survival (OS) in patients treated with oxaliplatin-based chemotherapy 3 months Overall Survival (OS) in patients treated with oxaliplatin-based chemotherapy according to MGMT methylation status. Overall Survival (OS) is defined as the time from random assignment to the date of death due to any cause, or to the date of censoring at the last time the subject was known to be alive in intention-to-treat populations
Objective Response (OR) in patients treated with oxaliplatin-based chemotherapy 3 months Objective Response (OR) in NETs patients treated with oxaliplatin-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).
Trial Locations
- Locations (19)
Centre Oscar Lambret
馃嚝馃嚪Lille, France
H么pital Nord - CHU Saint Etienne
馃嚝馃嚪Saint-Priest-en-Jarez, France
H么pital Beaujon - APHP
馃嚝馃嚪Clichy, France
H么pital Robert Debr茅 - CHU Reims
馃嚝馃嚪Reims, France
Institut Paoli Calmettes
馃嚝馃嚪Marseille, France
CH Annecy Genevois
馃嚝馃嚪Pringy, France
H么pital Cochin - APHP
馃嚝馃嚪Paris, France
H么pital Claude Hurriet - CHRU Lille
馃嚝馃嚪Lille, France
H么pital Trousseau - CHU Tours
馃嚝馃嚪Tours, France
H么pital Rangueil - CHU Toulouse
馃嚝馃嚪Toulouse, France
Institut Gustave Roussy
馃嚝馃嚪Villejuif, France
H么pital Sud - CHU Amiens
馃嚝馃嚪Amiens, France
H么pital Fran莽ois Mitterrand - CHU Dijon Bourgogne
馃嚝馃嚪Dijon, France
CHU d'Angers
馃嚝馃嚪Angers, France
H么pital Estaing, CHU de Clermont-Ferrand
馃嚝馃嚪Clermont-Ferrand, France
H么pital Edouard Herriot - Hospices Civils de Lyon
馃嚝馃嚪Lyon, France
H么pital Priv茅 Jean Mermoz
馃嚝馃嚪Lyon, France
Institut de Canc茅rologie de la Loire
馃嚝馃嚪Saint-Priest-en-Jarez, France
H么pital Saint Louis - APHP
馃嚝馃嚪Paris, France