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

Primary Purpose

Neuroendocrine Tumors

Status
Completed
Phase
Not Applicable
Locations
France
Study Type
Interventional
Intervention
Oxaliplatin-based chemotherapy
Alkylating-based chemotherapy
Sponsored by
Hospices Civils de Lyon
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Neuroendocrine Tumors focused on measuring Neuroendocrine tumors, Methylation MGMT status, Alkylating agents, Oxaliplatin

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • Hôpital Sud - CHU Amiens
  • CHU d'Angers
  • Hôpital Estaing, CHU de Clermont-Ferrand
  • Hôpital Beaujon - APHP
  • Hôpital François Mitterrand - CHU Dijon Bourgogne
  • Centre Oscar Lambret
  • Hôpital Claude Hurriet - CHRU Lille
  • Hôpital Edouard Herriot - Hospices Civils de Lyon
  • Hôpital Privé Jean Mermoz
  • Institut Paoli Calmettes
  • Hôpital Saint Louis - APHP
  • Hôpital Cochin - APHP
  • CH Annecy Genevois
  • Hôpital Robert Debré - CHU Reims
  • Hôpital Nord - CHU Saint Etienne
  • Institut de Cancérologie de la Loire
  • Hôpital Rangueil - CHU Toulouse
  • Hôpital Trousseau - CHU Tours
  • Institut Gustave Roussy

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Active Comparator

Experimental

Active Comparator

Arm Label

Unmethylated MGMT NET - OX

Unmethylated MGMT NET - ALKY

Methylated MGMT NET - OX

Methylated MGMT NET - ALKY

Arm Description

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).

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).

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).

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).

Outcomes

Primary Outcome Measures

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).

Secondary Outcome Measures

Objective Response (OR) in patients treated with oxaliplatin-based chemotherapy
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).
Progression Free Survival (PFS) in patients treated with alkylating-based chemotherapy
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.
Progression Free Survival (PFS) in patients treated with oxaliplatin-based chemotherapy
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.
Overall Survival (OS) in patients treated with alkylating-based chemotherapy
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
Overall Survival (OS) in patients treated with oxaliplatin-based chemotherapy
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
Objective Response (OR) assessed by immunochemistry on tissue
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

Full Information

First Posted
July 12, 2017
Last Updated
November 3, 2022
Sponsor
Hospices Civils de Lyon
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1. Study Identification

Unique Protocol Identification Number
NCT03217097
Brief Title
MGMT-NET: O6-methylguanine-DNA Methyltransferase (MGMT) Status in Neuroendocrine Tumors: Predictive Factor of Response to Alkylating Agents
Acronym
MGMT-NET
Official Title
MGMT-NET: O6-methylguanine-DNA Methyltransferase (MGMT) Status in Neuroendocrine Tumors: Predictive Factor of Response to Alkylating Agents
Study Type
Interventional

2. Study Status

Record Verification Date
November 2022
Overall Recruitment Status
Completed
Study Start Date
October 16, 2018 (Actual)
Primary Completion Date
January 31, 2022 (Actual)
Study Completion Date
April 25, 2022 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Hospices Civils de Lyon

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Neuroendocrine Tumors
Keywords
Neuroendocrine tumors, Methylation MGMT status, Alkylating agents, Oxaliplatin

7. Study Design

Primary Purpose
Treatment
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
116 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Unmethylated MGMT NET - OX
Arm Type
Experimental
Arm Description
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).
Arm Title
Unmethylated MGMT NET - ALKY
Arm Type
Active Comparator
Arm Description
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).
Arm Title
Methylated MGMT NET - OX
Arm Type
Experimental
Arm Description
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).
Arm Title
Methylated MGMT NET - ALKY
Arm Type
Active Comparator
Arm Description
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).
Intervention Type
Drug
Intervention Name(s)
Oxaliplatin-based chemotherapy
Intervention Description
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
Intervention Name(s)
Alkylating-based chemotherapy
Intervention Description
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 Measure Information:
Title
Objective Response (OR) in patients treated with alkylating-based chemotherapy
Description
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).
Time Frame
3 months
Secondary Outcome Measure Information:
Title
Objective Response (OR) in patients treated with oxaliplatin-based chemotherapy
Description
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).
Time Frame
3 months
Title
Progression Free Survival (PFS) in patients treated with alkylating-based chemotherapy
Description
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.
Time Frame
3 months
Title
Progression Free Survival (PFS) in patients treated with oxaliplatin-based chemotherapy
Description
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.
Time Frame
3 months
Title
Overall Survival (OS) in patients treated with alkylating-based chemotherapy
Description
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
Time Frame
3 months
Title
Overall Survival (OS) in patients treated with oxaliplatin-based chemotherapy
Description
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
Time Frame
3 months
Title
Objective Response (OR) assessed by immunochemistry on tissue
Description
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
Time Frame
3 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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.
Facility Information:
Facility Name
Hôpital Sud - CHU Amiens
City
Amiens
ZIP/Postal Code
80054
Country
France
Facility Name
CHU d'Angers
City
Angers
ZIP/Postal Code
49933
Country
France
Facility Name
Hôpital Estaing, CHU de Clermont-Ferrand
City
Clermont-Ferrand
ZIP/Postal Code
63003
Country
France
Facility Name
Hôpital Beaujon - APHP
City
Clichy
ZIP/Postal Code
92118
Country
France
Facility Name
Hôpital François Mitterrand - CHU Dijon Bourgogne
City
Dijon
ZIP/Postal Code
21000
Country
France
Facility Name
Centre Oscar Lambret
City
Lille
ZIP/Postal Code
59020
Country
France
Facility Name
Hôpital Claude Hurriet - CHRU Lille
City
Lille
ZIP/Postal Code
59037
Country
France
Facility Name
Hôpital Edouard Herriot - Hospices Civils de Lyon
City
Lyon
ZIP/Postal Code
69003
Country
France
Facility Name
Hôpital Privé Jean Mermoz
City
Lyon
ZIP/Postal Code
69008
Country
France
Facility Name
Institut Paoli Calmettes
City
Marseille
ZIP/Postal Code
13009
Country
France
Facility Name
Hôpital Saint Louis - APHP
City
Paris
ZIP/Postal Code
75010
Country
France
Facility Name
Hôpital Cochin - APHP
City
Paris
ZIP/Postal Code
75014
Country
France
Facility Name
CH Annecy Genevois
City
Pringy
ZIP/Postal Code
74374
Country
France
Facility Name
Hôpital Robert Debré - CHU Reims
City
Reims
ZIP/Postal Code
51092
Country
France
Facility Name
Hôpital Nord - CHU Saint Etienne
City
Saint-Priest-en-Jarez
ZIP/Postal Code
42270
Country
France
Facility Name
Institut de Cancérologie de la Loire
City
Saint-Priest-en-Jarez
ZIP/Postal Code
42270
Country
France
Facility Name
Hôpital Rangueil - CHU Toulouse
City
Toulouse
ZIP/Postal Code
31059
Country
France
Facility Name
Hôpital Trousseau - CHU Tours
City
Tours
ZIP/Postal Code
37044
Country
France
Facility Name
Institut Gustave Roussy
City
Villejuif
ZIP/Postal Code
94805
Country
France

12. IPD Sharing Statement

Citations:
PubMed Identifier
30824408
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.
Results Reference
derived

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

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