Clinical trial NCT03217097: MGMT-NET: O6-methylguanine-DNA Methyltransferase (MGMT) Status in Neuroendocrine Tumors: Predictive Factor of Response to Alkylating Agents
Official title: MGMT-NET: O6-methylguanine-DNA Methyltransferase (MGMT) Status in Neuroendocrine Tumors: Predictive Factor of Response to Alkylating Agents
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Neuroendocrine Tumors
Keywords: Neuroendocrine tumors
Methylation MGMT status
Alkylating agents
Oxaliplatin
Lead sponsor: Hospices Civils de Lyon
Sponsor class: OTHER
First posted: 2017-07-13
Enrollment: 116
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


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.

Primary outcomes:
measure: Objective Response (OR) in patients treated with alkylating-based chemotherapy
timeFrame: 3 months
Secondary outcomes:
measure: Objective Response (OR) in patients treated with oxaliplatin-based chemotherapy
timeFrame: 3 months
measure: Progression Free Survival (PFS) in patients treated with alkylating-based chemotherapy
timeFrame: 3 months
measure: Progression Free Survival (PFS) in patients treated with oxaliplatin-based chemotherapy
timeFrame: 3 months
measure: Overall Survival (OS) in patients treated with alkylating-based chemotherapy
timeFrame: 3 months
measure: Overall Survival (OS) in patients treated with oxaliplatin-based chemotherapy
timeFrame: 3 months
measure: Objective Response (OR) assessed by immunochemistry on tissue
timeFrame: 3 months
Other outcomes:
Locations:
city: Amiens
country: France
facility: Hôpital Sud - CHU Amiens
city: Angers
country: France
facility: CHU d'Angers
city: Clermont-Ferrand
country: France
facility: Hôpital Estaing, CHU de Clermont-Ferrand
city: Clichy
country: France
facility: Hôpital Beaujon - APHP
city: Dijon
country: France
facility: Hôpital François Mitterrand - CHU Dijon Bourgogne
city: Lille
country: France
facility: Centre Oscar Lambret
city: Lille
country: France
facility: Hôpital Claude Hurriet - CHRU Lille
city: Lyon
country: France
facility: Hôpital Edouard Herriot - Hospices Civils de Lyon
city: Lyon
country: France
facility: Hôpital Privé Jean Mermoz
city: Marseille
country: France
facility: Institut Paoli Calmettes
city: Paris
country: France
facility: Hôpital Saint Louis - APHP
city: Paris
country: France
facility: Hôpital Cochin - APHP
city: Pringy
country: France
facility: CH Annecy Genevois
city: Reims
country: France
facility: Hôpital Robert Debré - CHU Reims
city: Saint-Priest-en-Jarez
country: France
facility: Hôpital Nord - CHU Saint Etienne
city: Saint-Priest-en-Jarez
country: France
facility: Institut de Cancérologie de la Loire
city: Toulouse
country: France
facility: Hôpital Rangueil - CHU Toulouse
city: Tours
country: France
facility: Hôpital Trousseau - CHU Tours
city: Villejuif
country: France
facility: Institut Gustave Roussy
Study officials:
References:
citation: 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.