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

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ClinicalTrials.gov Identifier: NCT03217097
Recruitment Status : Recruiting
First Posted : July 13, 2017
Last Update Posted : February 28, 2019
Sponsor:
Information provided by (Responsible Party):
Hospices Civils de Lyon

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.


Condition or disease Intervention/treatment Phase
Neuroendocrine Tumors Drug: Oxaliplatin-based chemotherapy Drug: Alkylating-based chemotherapy Not Applicable

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 10 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: MGMT-NET: O6-methylguanine-DNA Methyltransferase (MGMT) Status in Neuroendocrine Tumors: Predictive Factor of Response to Alkylating Agents
Actual Study Start Date : October 16, 2018
Estimated Primary Completion Date : July 2021
Estimated Study Completion Date : November 2021

Resource links provided by the National Library of Medicine

Drug Information available for: Oxaliplatin

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).

Drug: 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).

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).

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).

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).

Drug: 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).

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).

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).




Primary Outcome Measures :
  1. Objective Response (OR) in patients treated with alkylating-based chemotherapy [ Time Frame: 3 months ]
    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).


Secondary Outcome Measures :
  1. Objective Response (OR) in patients treated with oxaliplatin-based chemotherapy [ Time Frame: 3 months ]
    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).

  2. 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.

  3. 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.

  4. Overall Survival (OS) in patients treated with alkylating-based chemotherapy [ Time Frame: 3 months ]
    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

  5. 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

  6. Objective Response (OR) assessed by immunochemistry on tissue [ Time Frame: 3 months ]
    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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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Age greater than or equal to 18 years;
  • Well-differentiated advanced grade 1-3 duodeno-pancreatic NETs, lung NETs (carcinoids) and unknown primary NETs;
  • 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 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03217097


Contacts
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Contact: Thomas WALTER, MD 4 72 11 96 93 ext +33 thomas.walter@chu-lyon.fr
Contact: Stéphanie VICENTE, MD 4 72 11 57 39 ext +33 stephanie.vicente@chu-lyon.fr

Locations
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France
Hôpital Sud - CHU Amiens Recruiting
Amiens, France, 80054
Contact: Vincent HAUTEFEUILLE, MD         
Principal Investigator: Vincent HAUTEFEUILLE, MD         
CHU d'Angers Recruiting
Angers, France, 49933
Contact: Sandrine LABOUREAU, MD         
Principal Investigator: Sandrine LABOUREAU, MD         
Hôpital Beaujon - APHP Recruiting
Clichy, France, 92118
Contact: Olivia HENTIC, MD         
Principal Investigator: Olivia HENTIC, MD         
Hôpital François Mitterrand - CHU Dijon Bourgogne Recruiting
Dijon, France, 21000
Contact: Côme LEPAGE, MD         
Principal Investigator: Côme LEPAGE, MD         
Hôpital André Michalon - CHU Grenoble Alpes Recruiting
La Tronche, France, 38700
Contact: Victoire GRANGER, MD         
Principal Investigator: Victoire GRANGER, MD         
Centre Oscar Lambret Recruiting
Lille, France, 59020
Contact: Eric DANSIN, MD         
Principal Investigator: Eric DANSIN, MD         
Hôpital Claude Hurriet - CHRU Lille Recruiting
Lille, France, 59037
Contact: Christine DO CAO, MD         
Principal Investigator: Christine DO CAO, MD         
Hôpital Edouard Herriot - Hospices Civils de Lyon Recruiting
Lyon, France, 69003
Contact: Thomas WALTER, MD         
Principal Investigator: Catherine LOMBARD BOHAS, MD         
Sub-Investigator: Thomas WALTER, MD         
Hôpital Privé Jean Mermoz Recruiting
Lyon, France, 69008
Contact: Jérôme DESRAMES, MD         
Principal Investigator: Jérôme DESRAMES, MD         
Centre Léon Bérard Recruiting
Lyon, France, 69373
Contact: Matthieu SARABI, MD         
Principal Investigator: Matthieu SARABI, MD         
Institut Paoli Calmettes Recruiting
Marseille, France, 13009
Contact: Patricia NICCOLI, MD         
Principal Investigator: Patricia NICCOLI, MD         
Hôpital Saint Eloi - CHU Montpellier Recruiting
Montpellier, France, 34090
Contact: Eric ASSENAT, MD         
Principal Investigator: Eric ASSENAT, MD         
Hôpital Saint Louis - APHP Recruiting
Paris, France, 75010
Contact: Thomas APARICIO, MD         
Principal Investigator: Thomas APARICIO, MD         
Hôpital Cochin - APHP Recruiting
Paris, France, 75014
Contact: Romain CORIAT, MD         
Principal Investigator: Romain CORIAT, MD         
CH Annecy Genevois Recruiting
Pringy, France, 74374
Contact: Mathieu BACONNIER, MD         
Principal Investigator: Mathieu BACONNIER, MD         
Hôpital Robert Debré - CHU Reims Recruiting
Reims, France, 51092
Contact: Guillaume CADIOT, MD         
Principal Investigator: Guillaume CADIOT, MD         
Hôpital Nord - CHU Saint Etienne Recruiting
Saint-Priest-en-Jarez, France, 42270
Contact: Nicolas WILLIET, MD         
Principal Investigator: Nicolas WILLIET, MD         
Institut de Cancérologie de la Loire Recruiting
Saint-Priest-en-Jarez, France, 42270
Contact: Léa SABAN-ROCHE, MD         
Principal Investigator: Léa SABAN-ROCHE, MD         
Hôpital Rangueil - CHU Toulouse Recruiting
Toulouse, France, 31059
Contact: Rosine GUIMBAUD, MD         
Principal Investigator: Rosine GUIMBAUD, MD         
Hôpital Trousseau - CHU Tours Recruiting
Tours, France, 37044
Contact: Thierry LECOMTE, MD         
Principal Investigator: Thierry LECOMTE, MD         
Institut Gustave Roussy Recruiting
Villejuif, France, 94805
Contact: Eric BAUDIN, MD         
Principal Investigator: Eric BAUDIN, MD         
Sponsors and Collaborators
Hospices Civils de Lyon

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Hospices Civils de Lyon
ClinicalTrials.gov Identifier: NCT03217097     History of Changes
Other Study ID Numbers: 69HCL17_0284
First Posted: July 13, 2017    Key Record Dates
Last Update Posted: February 28, 2019
Last Verified: January 2019

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Hospices Civils de Lyon:
Neuroendocrine tumors
Methylation MGMT status
Alkylating agents
Oxaliplatin
Additional relevant MeSH terms:
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Neuroendocrine Tumors
Neoplasms
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms, Nerve Tissue
Leucovorin
Gemcitabine
Capecitabine
Fluorouracil
Oxaliplatin
Temozolomide
Streptozocin
Alkylating Agents
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Antiviral Agents
Anti-Infective Agents
Enzyme Inhibitors
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antineoplastic Agents, Alkylating
Antidotes
Protective Agents
Vitamin B Complex
Vitamins
Micronutrients