Ignite Creation Date:
2024-05-06 @ 9:00 AM
Last Modification Date:
2024-10-26 @ 12:08 PM
Study NCT ID:
NCT02876081
Status:
WITHDRAWN
Last Update Posted:
2017-09-11
First Post:
2016-08-18
Brief Title:
Phase II Study of Afatinib as Third- or Further-line Treatment for Patients With Stage IV Bronchial Adenocarcinoma Harboring Wild-type EGFR Expressing the Neurotensin - Neurotensin Receptor Complex
Sponsor:
Fondation Hôpital Saint-Joseph
Organization:
Fondation Hôpital Saint-Joseph
Study Overview
Official Title:
Phase II Study of Afatinib as Third- or Further-line Treatment for Patients With Stage IV Bronchial Adenocarcinoma Harboring Wild-type EGFR Expressing the Neurotensin - Neurotensin Receptor Complex
Status:
WITHDRAWN
Status Verified Date:
2017-09
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
medical decision
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
THEN
Brief Summary:
Lung cancer is the leading cause of cancer deaths in France Europe and the world 50 of lung cancers are of the adenocarcinoma subtype 60 of patients present with a metastatic disease stage IV at the time of diagnosis Approximately 10 of patients present with a mutation of the epidermal growth factor receptor EGFR requiring an EGFR tyrosine kinase inhibitor EGFR-TKI namely erlotinib gefitinib or afatinib For the majority of chemotherapy-naïve patients without addictive mutation platinum-based chemotherapy frequently the platinum - pemetrexed doublet provides disease control rate of up to 70 and improves survival from approximately 45 with best supportive care alone to 15 months However patients with non-small cell lung cancer NSCLC usually relapse within 4 to 6 months and benefit from a second-line chemotherapy Authorized drugs in this setting are pemetrexed docetaxel and erlotinib The prescription of erlotinib for unselected patients whose tumor does not harbor an EGFR mutation is questionable In the second line setting docetaxel provides less than 10 of partial responses and progression-free survival of 10 to 12 weeks There are no standard options following failure of two previous lines of standard chemotherapy In view of these modest results new agents and therapeutic strategies are greatly needed for this patient population
Neurotensin NTS is a 13 amino acids peptide present and biologically active in the central nervous system and in periphery At the peripheral level NTS is released by the endocrine cells of the intestinal mucosa after meals and acts as an endocrine hormone involved in the postprandial regulation of the motor functions of the gastrointestinal tract The effects of NTS are mediated by three subtypes of receptor NTSR1 and NTSR2 exhibit high and low affinity for NTS respectively and belong to the family of G protein receptors NTSR3 is a single transmembrane domain receptor Exogenous activation of NTSR1 leads to cell proliferation survival mobility and invasion in cancer cells from diverse origin These effects are the result from the activation of kinases and effectors such as PKC MAPK FAK RHO-GTPase RAS and Src The PKC activation may induce MAPK by direct stimulation of Raf-1 or by transactivation of the EGFR The activation of MAPK via NTSR1 is mainly associated with uncontrolled cell growth Both NTS and NTSR1 are expressed in 40 of lung tumors whereas they are never expressed in the normal tissue NTSR1 high expression is a negative prognostic factor in stage I to III operated lung adenocarcinomas Sustained stimulation of NTSR1 results in the activation of MMP1 the release of EGF like ligands such as HB-EGF as well as neuregulin 1 NGR1 a specific ligand for HER3 followed by EGFR HER2 and HER3 overexpression and activation Accordingly xenografted tumors expressing NTS and NTSR1 show a positive response to erlotinib whereas tumors void of NTSR1 expression have no detectable response
Afatinib BIBW2992 is a small molecule selective and irreversible erbB family blocker In preclinical models it effectively inhibits EGFR HER2 and HER4 phosphorylation resulting in tumour growth inhibition and regression of established subcutaneous tumours derived from four human cell-lines known to co-express ErbB receptors
Our claim is that patients harbouring the NTSNTSR complex without EGFR mutation will respond to afatinib due to the sustained activation of EGFRHER2 under neurotensin activation
Presently only EGFR mutated tumors are eligible to receive EGFR TKI representing 10 of all lung cancer patients The aim of this study is to evaluate the efficacy of afatinib an EGFR TKI on lung adenocarcinomas EGFR wild-type bearing the NTSNTSR1 complex with a high level of expression This subpopulation of patients represents approximately 20 of lung adenocarcinomas
Neurotensin NTS is a 13 amino acids peptide present and biologically active in the central nervous system and in periphery At the peripheral level NTS is released by the endocrine cells of the intestinal mucosa after meals and acts as an endocrine hormone involved in the postprandial regulation of the motor functions of the gastrointestinal tract The effects of NTS are mediated by three subtypes of receptor NTSR1 and NTSR2 exhibit high and low affinity for NTS respectively and belong to the family of G protein receptors NTSR3 is a single transmembrane domain receptor Exogenous activation of NTSR1 leads to cell proliferation survival mobility and invasion in cancer cells from diverse origin These effects are the result from the activation of kinases and effectors such as PKC MAPK FAK RHO-GTPase RAS and Src The PKC activation may induce MAPK by direct stimulation of Raf-1 or by transactivation of the EGFR The activation of MAPK via NTSR1 is mainly associated with uncontrolled cell growth Both NTS and NTSR1 are expressed in 40 of lung tumors whereas they are never expressed in the normal tissue NTSR1 high expression is a negative prognostic factor in stage I to III operated lung adenocarcinomas Sustained stimulation of NTSR1 results in the activation of MMP1 the release of EGF like ligands such as HB-EGF as well as neuregulin 1 NGR1 a specific ligand for HER3 followed by EGFR HER2 and HER3 overexpression and activation Accordingly xenografted tumors expressing NTS and NTSR1 show a positive response to erlotinib whereas tumors void of NTSR1 expression have no detectable response
Afatinib BIBW2992 is a small molecule selective and irreversible erbB family blocker In preclinical models it effectively inhibits EGFR HER2 and HER4 phosphorylation resulting in tumour growth inhibition and regression of established subcutaneous tumours derived from four human cell-lines known to co-express ErbB receptors
Our claim is that patients harbouring the NTSNTSR complex without EGFR mutation will respond to afatinib due to the sustained activation of EGFRHER2 under neurotensin activation
Presently only EGFR mutated tumors are eligible to receive EGFR TKI representing 10 of all lung cancer patients The aim of this study is to evaluate the efficacy of afatinib an EGFR TKI on lung adenocarcinomas EGFR wild-type bearing the NTSNTSR1 complex with a high level of expression This subpopulation of patients represents approximately 20 of lung adenocarcinomas
Detailed Description:
None
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None