MGMT-NET: O6-methylguanine-DNA Methyltransferase (MGMT) Status in Neuroendocrine Tumors: Predictive Factor of Response to Alkylating Agents

Study Overview
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Brief Summary
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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.

Official Title
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MGMT-NET: O6-methylguanine-DNA Methyltransferase (MGMT) Status in Neuroendocrine Tumors: Predictive Factor of Response to Alkylating Agents

Conditions
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Neuroendocrine Tumors

Intervention / Treatment
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* Drug: Oxaliplatin-based chemotherapy
* Drug: Alkylating-based chemotherapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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. Exclusion Criteria: 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Unmethylated MGMT NET - OX<br>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). | Drug: Oxaliplatin-based chemotherapy<br>* 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).<br>|
| Active Comparator: Unmethylated MGMT NET - ALKY<br>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). | Drug: Alkylating-based chemotherapy<br>* 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).<br>|
| Experimental: Methylated MGMT NET - OX<br>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). | Drug: Oxaliplatin-based chemotherapy<br>* 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).<br>|
| Active Comparator: Methylated MGMT NET - ALKY<br>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). | Drug: Alkylating-based chemotherapy<br>* 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).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response (OR) in patients treated with alkylating-based chemotherapy | 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). | 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response (OR) in patients treated with oxaliplatin-based chemotherapy | 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). | 3 months | 
| Progression Free Survival (PFS) in patients treated with alkylating-based chemotherapy | 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. | 3 months | 
| Progression Free Survival (PFS) in patients treated with oxaliplatin-based chemotherapy | 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. | 3 months | 
| Overall Survival (OS) in patients treated with alkylating-based chemotherapy | 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 | 3 months | 
| Overall Survival (OS) in patients treated with oxaliplatin-based chemotherapy | 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 | 3 months | 
| Objective Response (OR) assessed by immunochemistry on tissue | 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 | 3 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Neuroendocrine tumors, Methylation MGMT status, Alkylating agents, Oxaliplatin