- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT03217097
MGMT-NET: O6-methylguanine-DNA Methyltransferase (MGMT) Status in Neuroendocrine Tumors: Predictive Factor of Response to Alkylating Agents (MGMT-NET)
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.
Study Overview
Status
Conditions
Intervention / Treatment
Study Type
Enrollment (Actual)
Phase
- Not Applicable
Contacts and Locations
Study Locations
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Amiens, France, 80054
- Hôpital Sud - CHU Amiens
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Angers, France, 49933
- CHU d'Angers
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Clermont-Ferrand, France, 63003
- Hôpital Estaing, CHU de Clermont-Ferrand
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Clichy, France, 92118
- Hôpital Beaujon - APHP
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Dijon, France, 21000
- Hôpital François Mitterrand - CHU Dijon Bourgogne
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Lille, France, 59020
- Centre Oscar Lambret
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Lille, France, 59037
- Hôpital Claude Hurriet - CHRU Lille
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Lyon, France, 69008
- Hopital Prive Jean Mermoz
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Lyon, France, 69003
- Hôpital Edouard Herriot - Hospices civils de Lyon
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Marseille, France, 13009
- Institut Paoli Calmettes
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Paris, France, 75014
- Hôpital Cochin - APHP
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Paris, France, 75010
- Hôpital Saint Louis - APHP
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Pringy, France, 74374
- CH Annecy Genevois
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Reims, France, 51092
- Hôpital Robert Debré - CHU Reims
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Saint-Priest-en-Jarez, France, 42270
- Institut de Cancérologie de la Loire
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Saint-Priest-en-Jarez, France, 42270
- Hôpital Nord - CHU Saint Etienne
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Toulouse, France, 31059
- Hôpital Rangueil - CHU Toulouse
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Tours, France, 37044
- Hopital Trousseau - CHU Tours
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Villejuif, France, 94805
- Institut Gustave Roussy
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
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.
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: 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). |
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).
|
Active Comparator: 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). |
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).
|
Experimental: 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). |
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).
|
Active Comparator: 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). |
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).
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Objective Response (OR) in patients treated with alkylating-based chemotherapy
Time Frame: 3 months
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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).
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3 months
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Objective Response (OR) in patients treated with oxaliplatin-based chemotherapy
Time Frame: 3 months
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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).
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3 months
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Progression Free Survival (PFS) in patients treated with alkylating-based chemotherapy
Time Frame: 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.
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3 months
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Progression Free Survival (PFS) in patients treated with oxaliplatin-based chemotherapy
Time Frame: 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.
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3 months
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Overall Survival (OS) in patients treated with alkylating-based chemotherapy
Time Frame: 3 months
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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
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3 months
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Overall Survival (OS) in patients treated with oxaliplatin-based chemotherapy
Time Frame: 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
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3 months
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Objective Response (OR) assessed by immunochemistry on tissue
Time Frame: 3 months
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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
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3 months
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Collaborators and Investigators
Sponsor
Publications and helpful links
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
Other Study ID Numbers
- 69HCL17_0284
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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