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

NCT03217097 | Completed DMC

• 1 other identifier: 69HCL17_0284
• Study Type: interventional
• Target: 116
• Locations: 1 country
• Sites: 19

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

Keywords

Neuroendocrine tumors; Methylation MGMT status; Alkylating agents; Oxaliplatin

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (6)

• Objective Response (OR) in patients treated with oxaliplatin-based chemotherapy

  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

Study Arms (4)

Unmethylated MGMT NET - OX

EXPERIMENTAL

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

Unmethylated MGMT NET - ALKY

ACTIVE COMPARATOR

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

Methylated MGMT NET - OX

EXPERIMENTAL

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

Methylated MGMT NET - ALKY

ACTIVE COMPARATOR

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

Interventions

Oxaliplatin-based chemotherapy 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 - OX; Unmethylated MGMT NET - OX

Alkylating-based chemotherapy 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 - ALKY; Unmethylated MGMT NET - ALKY

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Hospices Civils de Lyon: lead

Study Sites (19)

Hôpital Sud - CHU Amiens

Amiens, 80054, France

Location

CHU d'Angers

Angers, 49933, France

Location

Hôpital Estaing, CHU de Clermont-Ferrand

Clermont-Ferrand, 63003, France

Location

Hôpital Beaujon - APHP

Clichy, 92118, France

Location

Hôpital François Mitterrand - CHU Dijon Bourgogne

Dijon, 21000, France

Location

Centre Oscar Lambret

Lille, 59020, France

Location

Hôpital Claude Hurriet - CHRU Lille

Lille, 59037, France

Location

Hôpital Edouard Herriot - Hospices Civils de Lyon

Lyon, 69003, France

Location

Hôpital Privé Jean Mermoz

Lyon, 69008, France

Location

Institut Paoli Calmettes

Marseille, 13009, France

Location

Hôpital Saint Louis - APHP

Paris, 75010, France

Location

Hôpital Cochin - APHP

Paris, 75014, France

Location

CH Annecy Genevois

Pringy, 74374, France

Location

Hôpital Robert Debré - CHU Reims

Reims, 51092, France

Location

Hôpital Nord - CHU Saint Etienne

Saint-Priest-en-Jarez, 42270, France

Location

Institut de Cancérologie de la Loire

Saint-Priest-en-Jarez, 42270, France

Location

Hôpital Rangueil - CHU Toulouse

Toulouse, 31059, France

Location

Hôpital Trousseau - CHU Tours

Tours, 37044, France

Location

Institut Gustave Roussy

Villejuif, 94805, France

Location

Related Publications (2)

• 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.

  PMID: 30824408 RESULT

• 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.

  PMID: 39586038 RESULT

MeSH Terms

Conditions

Neuroendocrine Tumors

Condition Hierarchy (Ancestors)

Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Nerve Tissue

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 12, 2017
• First Posted: July 13, 2017
• Study Start: October 16, 2018
• Primary Completion: January 31, 2022
• Study Completion: April 25, 2022
• Last Updated: November 21, 2025

Record last verified: 2022-11

Locations

FR (19)