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

NCT ID: NCT03217097

Last Updated: 2025-11-21

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: NA
• Total Enrollment: 116 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2018-10-16
• Study Completion Date: 2022-04-25

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.

Conditions

Neuroendocrine Tumors

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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).

Group Type: EXPERIMENTAL

Oxaliplatin-based chemotherapy

Intervention Type: DRUG

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).

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).

Group Type: ACTIVE_COMPARATOR

Alkylating-based chemotherapy

Intervention Type: DRUG

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).

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).

Group Type: EXPERIMENTAL

Oxaliplatin-based chemotherapy

Intervention Type: DRUG

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 - 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).

Group Type: ACTIVE_COMPARATOR

Alkylating-based chemotherapy

Intervention Type: DRUG

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).

Interventions

Oxaliplatin-based chemotherapy

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).

Intervention Type: DRUG

Alkylating-based chemotherapy

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).

Intervention Type: DRUG

Eligibility Criteria

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Hospices Civils de Lyon

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Locations

Hôpital Sud - CHU Amiens

Amiens, , France

CHU d'Angers

Angers, , France

Hôpital Estaing, CHU de Clermont-Ferrand

Clermont-Ferrand, , France

Hôpital Beaujon - APHP

Clichy, , France

Hôpital François Mitterrand - CHU Dijon Bourgogne

Dijon, , France

Centre Oscar Lambret

Lille, , France

Hôpital Claude Hurriet - CHRU Lille

Lille, , France

Hôpital Edouard Herriot - Hospices Civils de Lyon

Lyon, , France

Hôpital Privé Jean Mermoz

Lyon, , France

Institut Paoli Calmettes

Marseille, , France

Hôpital Saint Louis - APHP

Paris, , France

Hôpital Cochin - APHP

Paris, , France

CH Annecy Genevois

Pringy, , France

Hôpital Robert Debré - CHU Reims

Reims, , France

Hôpital Nord - CHU Saint Etienne

Saint-Priest-en-Jarez, , France

Institut de Cancérologie de la Loire

Saint-Priest-en-Jarez, , France

Hôpital Rangueil - CHU Toulouse

Toulouse, , France

Hôpital Trousseau - CHU Tours

Tours, , France

Institut Gustave Roussy

Villejuif, , France

Countries

France

References

Lemelin A, Barritault M, Hervieu V, Payen L, Peron J, Couvelard A, Cros J, Scoazec JY, Bin S, Villeneuve L, Lombard-Bohas C, Walter T; MGMT-NET investigators. O6-methylguanine-DNA methyltransferase (MGMT) status in neuroendocrine tumors: a randomized phase II study (MGMT-NET). Dig Liver Dis. 2019 Apr;51(4):595-599. doi: 10.1016/j.dld.2019.02.001. Epub 2019 Feb 14.

Reference Type: RESULT

PMID: 30824408 (View on PubMed)

Walter T, Lecomte T, Hadoux J, Niccoli P, Saban-Roche L, Gaye E, Guimbaud R, Baconnier M, Hautefeuille V, Do Cao C, Petorin C, Hentic O, Perrier M, Aparicio T, Scoazec JY, Bonjour M, Gibert B, Hervieu V, Poncet D, Barritault M, Gerard L, Durand A; "Groupe d'etude des tumeurs endocrines (GTE)" and the French ENDOCAN-RENATEN network. Oxaliplatin-Based Versus Alkylating Agent in Neuroendocrine Tumors According to the O6-Methylguanine-DNA Methyltransferase Status: A Randomized Phase II Study (MGMT-NET). J Clin Oncol. 2025 Mar 10;43(8):960-971. doi: 10.1200/JCO.23.02724. Epub 2024 Nov 25.

Reference Type: RESULT

PMID: 39586038 (View on PubMed)

Other Identifiers

69HCL17_0284

Identifier Type: -

Identifier Source: org_study_id