Ignite Creation Date:
2024-05-06 @ 9:48 AM
Last Modification Date:
2024-10-26 @ 12:19 PM
Study NCT ID:
NCT03071705
Status:
UNKNOWN
Last Update Posted:
2017-03-07
First Post:
2017-03-01
Brief Title:
Metformin Plus TKI Use in Patients With Non-Small Cell Lung Carcinoma
Sponsor:
Instituto Nacional de Cancerologia de Mexico
Organization:
Instituto Nacional de Cancerologia de Mexico
Study Overview
Official Title:
Effect of Metformin in Combination With Tyrosine Kinase Inhibitors TKI on Clinical Biochemical and Nutritional in Patients With Non-Small Cell Lung Carcinoma NSCLC Randomized Clinical Trial
Status:
UNKNOWN
Status Verified Date:
2017-03
Last Known Status:
RECRUITING
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Treatment for patients with mutation in the epidermal growth factor receptor EGFR with specific domain tyrosine kinase inhibitors TKIs has given place to objective clinical response increase in progression-free survival PFS compared to cytotoxic chemotherapy However despite clinical success with different TKIs most patients eventually develop acquired resistance to these agents after an average period of time of 10 months
Recently metformin an oral hypoglycemic agent has been associated with reduction in the global risk of incidence and mortality of different types of cancer by exercising anti-tumor properties Its role as a chemo-preventive and adjuvant drug in overcoming acquired resistance to chemotherapy target therapy and immunotherapy in NSCLC is still under discussion
However preclinical data support the role as an adjuvant drug in the treatment of NSCLC in combination with chemotherapy or EGFR-TKIs This evidence led to examine the effects of metformin in combination with EGFR-TKIs in a NSCLC cellular line panel obtaining a different sensibility to the unique use with EGFR-TKIs The combination of metformin and TKIs reduced the colony forming capacity and proliferation and induced a huge pro-apoptotic effect in NSCLC cellular lines and resistance in EGFR-TKIs This suggests that metformin may reduce the resistance to TKIs A retrospective study in patients from our institution from 2008 to 2014 showed significant clinical benefit in patients who used metformin improving the global survival Based on these considerations we propose a phase II randomized study to assess the effect and safety of metformin in combination with TKIs as second line therapy in patients with NSCLC in advanced stages with EGFR mutation
The main objective of this study is to assess the progression-free survival period in patients with advanced non-small cell lung cancer in treatment with TKIs and metformin versus TKI alone
Recently metformin an oral hypoglycemic agent has been associated with reduction in the global risk of incidence and mortality of different types of cancer by exercising anti-tumor properties Its role as a chemo-preventive and adjuvant drug in overcoming acquired resistance to chemotherapy target therapy and immunotherapy in NSCLC is still under discussion
However preclinical data support the role as an adjuvant drug in the treatment of NSCLC in combination with chemotherapy or EGFR-TKIs This evidence led to examine the effects of metformin in combination with EGFR-TKIs in a NSCLC cellular line panel obtaining a different sensibility to the unique use with EGFR-TKIs The combination of metformin and TKIs reduced the colony forming capacity and proliferation and induced a huge pro-apoptotic effect in NSCLC cellular lines and resistance in EGFR-TKIs This suggests that metformin may reduce the resistance to TKIs A retrospective study in patients from our institution from 2008 to 2014 showed significant clinical benefit in patients who used metformin improving the global survival Based on these considerations we propose a phase II randomized study to assess the effect and safety of metformin in combination with TKIs as second line therapy in patients with NSCLC in advanced stages with EGFR mutation
The main objective of this study is to assess the progression-free survival period in patients with advanced non-small cell lung cancer in treatment with TKIs and metformin versus TKI alone
Detailed Description:
Lung cancer is the first cause of death in men and women representing 28 and 26 of registered deaths worldwide respectively Among patients with this disease at least 80 has non-small cell lung cancer NSCLC and 60 of patients are diagnosed when they already have a locally advanced or metastatic disease NSCLC therapy regimens depend on the stage of disease and may require surgery chemotherapy radiotherapy or a combination of these Survival rate at 5 years is low for patients with stage II and III of the disease with variation from 30 to 5 this means that an improvement in therapy are required
Advances in molecular biology of cancer have led to discovering several molecular targets and developing new target therapies Epidermal growth factor receptor EGFR is involved in the development and progression of several types of cancer including NSCLC However despite clinical success with different tyrosine kinase specific domain inhibitors TKIs most of the patients respond to these drugs initially but eventually develop resistance to these drugs after and average period of time of 10 months Thus innovative treatment strategies are required urgently to overcome therapeutic resistance to EGFR-TKIs and to improve survival of patients with NSCLC
Recently metformin has been associated with reduction in the global risk of incidence and mortality of different types of cancer due to its anti-tumor properties In specific types of cancer retrospective studies have demonstrated a clinical benefit from the use of metformin combined with the treatment of cancer
Patients with NSCLC with positive EGFR mutations are highly sensible to specific anti-EGFR tyrosine kinase inhibitors however most of the patients who initially respond to these target therapies will present progression of the disease posteriorly during the treatment this is known as acquired resistance Acquired resistance to target therapies was first studied in patients with chronic myeloid leukemia with BCR-ABL translocation treated with Imitanib an inhibitor of aberrant kinase BCR-ABL Thanks to research mutations associated with resistance to treatment with TKIs in NSCLC with positive EGFR mutations were discovered By several studies additional mutations were found in the kinase domain and in KRAS in those patients with acquired resistance to Gefitinib or Erlotinib By PCR it was found that 50 of patients with resistance to TKI develop a specific mutation in exon 20 T790M However the mechanism by which the other 50 of patients develop resistance to anti-EGFR TKI is yet unknown Some studies have found focal amplification of MET proto-oncogen in 22 of the patients with acquired resistance to Gefitinib The proposed mechanism is that MET amplification promotes resistance by activation of HER3 depending PI3K pathway Nonetheless there are few studies with few patients about MET amplification as a resistance mechanism
On the other hand there are patients who have this resistance mutation since the first presentation or de novo T790M mutation may be present before exposition to TKI and its generally found with other activating mutations in EGFR exon 19 deletion and punctual L858R mutation A response rate of 8 has been reported in those patients treated with gefitinib or erlotinib whose T790M mutation was positive at the time of the diagnosis with progression-free survival of 2 months and global survival median of 16 months
Despite the advances in treatment have increased response rate and progression-free survival with anti-EGFR TKI in patients with presence of activating mutations most of them will develop resistance mutations T790M and disease progression There is no standard treatment in patients who progress from a first generation anti-EGFR TKI such as erlotinib and gefitinib Some studies have used afatinib as second line therapy in patients who had progression finding a benefit in the progression-free survival disease control rate up until 58 and delay in the development of lung cancer associate symptoms thus improving quality of life in patients treated with afatinib
Acquired resistance will develop in a mean time of 9 to 13 months and the 50 to 60 will be secondary to development of T790M resistance mutation
The molecular mechanisms that generate acquired resistance to anti-EGFR TKI are not completely clear We know that around 50 of cases are caused by an acquired mutation in the EGFR T790M and a lower percentage by MET oncogene amplification nevertheless there are other proposed molecular mechanisms such as the activation of mesenchymal-epithelial transition The latter refers to changes in the phenotype of epithelial cells to cells with mesenchymal cells phenotype resulting in increase in motility proliferation and metastasis of tumor cells Its been proposed that epithelial-mesenchymal EMT is associated with sensitivity to chemotherapy and TKI Finding an effective therapy for patients who develop T790M resistance mutation is required to overcome resistance to first generation anti-EGFR TKI Afatinib as a second generation irreversible anti-EGFR TKI has demonstrated in some studies to have certain effect in patients with resistance however the benefit is marginal Studies have shown that the union of the tyrosine kinase portion of afatinib in patients with resistance mutation is 100 times less strong that the union in cells with anti-EGFR activating mutations Pre-clinical studies have demonstrated that inhibition of IL-6 receptor activation and activation of JAK1STAT3 pathway overcomes resistance and sensitize again those cells with EGFR resistance mutation
Metformin is a drug that has been used for several years to treat diabetes mellitus and metabolic syndrome its generally well tolerated Several studies since 1910 have suggested that patients with diabetes are at increased risk to develop cancer The American Diabetes Association and The American Cancer Society have come to a consensus that suggests a clear association for greater risk of cancer incidence in diabetic patients The tumors that have been studied with more frequency are in colon endometrium rectus and breast On the other hand several epidemiologic and cases and control studies have suggested that the use of metformin decreases risk to develop cancer up until 30 with a hazard ratio HR of 077 064-092 and risk of cancer-specific death with a HR of 067 053-085 Such protective effect has been seen in all kinds of cancer but has been more studied in breast gastrointestinal and lung cancer
The effect of metformin as chemo-prevention is subject to debate however theres more information about its use as adjuvant in the treatment of lung cancer in combination with chemotherapy or target molecular therapy Pre-clinical studies in mice have demonstrated that use of metformin per os may decrease the necessary dosage of chemotherapy and may prolong tumor remission Metformin by inhibiting repairing and anti-apoptosis mechanisms increases sensitivity to chemotherapy especially to platinum Studies that involve metformin paclitaxel carboplatin and doxorubicin have demonstrated to have an effect in tumor regression and prevention of recurrences up until four times the effect of monotherapy in xenograft models in cellular lines of lung and prostate cancer Retrospective studies have found a benefit in progression-free survival and global survival in diabetic patients with NSCLC who also are treated with metformin
T790M mutation and MET amplification are the main resistance mechanisms to anti-EGFR TKI other mechanisms such as epithelial-mesenchymal transition EMT by TGF-β are resistance mechanisms TGF-β also induces activation of IL-6 and paracrine activation of the receptor IL-6R and at the same time the activation of pathway JAK1STAT3 and cell immortalization Pre-clinical studies with cellular lines of lung cancer with anti-EGFR acquired-resistance treatment show that metformin prevents transcription of factors that activate epithelial-mesenchymal transition inhibiting TGF-β thus inhibiting IL-6JAK1STAT3 pathway overcoming anti-EGFR TKI resistance in patients with T790M resistance mutation in vitro and in vivo A recent study reports that use of metformin in combination with gefitinib may increase efficacy of the latter showing anti-proliferative and pro-apoptotic effect in cellular lines of NSCLC Other studies have shown by Western-blot a decrease in levels of phosphorylation and activation of growth pathways MAPK AKT and mTOR with the use of metformin found in pre-clinical studies Currently a phase III study is being carried out to determine effective dose safety and posteriorly the activity of metformin in combination with erlotinib as second line therapy in patients with NSCLC without EGFR mutation
The main objective of this study is to assess the progression-free survival period in patients with advanced non-small cell lung cancer in treatment with TKIs and metformin versus TKI alone The secondary objectives are the response rate global survival quality of life safety as well as determining the alteration of nutrition parameters associated to the combined use of TKIs and metformin
Besides the secondary objectives we want to find new candidate markers in the tumor characteristics to predict anti-tumor activity as well as the search for serum biomarkers among which we will analyze EGFR mutations exon 18-21 mutations IL-6 IGF-1 as well as determination of LKB-1 molecule expression in tumor tissue We will associate the prognostic and potential role as possible biomarkers
Advances in molecular biology of cancer have led to discovering several molecular targets and developing new target therapies Epidermal growth factor receptor EGFR is involved in the development and progression of several types of cancer including NSCLC However despite clinical success with different tyrosine kinase specific domain inhibitors TKIs most of the patients respond to these drugs initially but eventually develop resistance to these drugs after and average period of time of 10 months Thus innovative treatment strategies are required urgently to overcome therapeutic resistance to EGFR-TKIs and to improve survival of patients with NSCLC
Recently metformin has been associated with reduction in the global risk of incidence and mortality of different types of cancer due to its anti-tumor properties In specific types of cancer retrospective studies have demonstrated a clinical benefit from the use of metformin combined with the treatment of cancer
Patients with NSCLC with positive EGFR mutations are highly sensible to specific anti-EGFR tyrosine kinase inhibitors however most of the patients who initially respond to these target therapies will present progression of the disease posteriorly during the treatment this is known as acquired resistance Acquired resistance to target therapies was first studied in patients with chronic myeloid leukemia with BCR-ABL translocation treated with Imitanib an inhibitor of aberrant kinase BCR-ABL Thanks to research mutations associated with resistance to treatment with TKIs in NSCLC with positive EGFR mutations were discovered By several studies additional mutations were found in the kinase domain and in KRAS in those patients with acquired resistance to Gefitinib or Erlotinib By PCR it was found that 50 of patients with resistance to TKI develop a specific mutation in exon 20 T790M However the mechanism by which the other 50 of patients develop resistance to anti-EGFR TKI is yet unknown Some studies have found focal amplification of MET proto-oncogen in 22 of the patients with acquired resistance to Gefitinib The proposed mechanism is that MET amplification promotes resistance by activation of HER3 depending PI3K pathway Nonetheless there are few studies with few patients about MET amplification as a resistance mechanism
On the other hand there are patients who have this resistance mutation since the first presentation or de novo T790M mutation may be present before exposition to TKI and its generally found with other activating mutations in EGFR exon 19 deletion and punctual L858R mutation A response rate of 8 has been reported in those patients treated with gefitinib or erlotinib whose T790M mutation was positive at the time of the diagnosis with progression-free survival of 2 months and global survival median of 16 months
Despite the advances in treatment have increased response rate and progression-free survival with anti-EGFR TKI in patients with presence of activating mutations most of them will develop resistance mutations T790M and disease progression There is no standard treatment in patients who progress from a first generation anti-EGFR TKI such as erlotinib and gefitinib Some studies have used afatinib as second line therapy in patients who had progression finding a benefit in the progression-free survival disease control rate up until 58 and delay in the development of lung cancer associate symptoms thus improving quality of life in patients treated with afatinib
Acquired resistance will develop in a mean time of 9 to 13 months and the 50 to 60 will be secondary to development of T790M resistance mutation
The molecular mechanisms that generate acquired resistance to anti-EGFR TKI are not completely clear We know that around 50 of cases are caused by an acquired mutation in the EGFR T790M and a lower percentage by MET oncogene amplification nevertheless there are other proposed molecular mechanisms such as the activation of mesenchymal-epithelial transition The latter refers to changes in the phenotype of epithelial cells to cells with mesenchymal cells phenotype resulting in increase in motility proliferation and metastasis of tumor cells Its been proposed that epithelial-mesenchymal EMT is associated with sensitivity to chemotherapy and TKI Finding an effective therapy for patients who develop T790M resistance mutation is required to overcome resistance to first generation anti-EGFR TKI Afatinib as a second generation irreversible anti-EGFR TKI has demonstrated in some studies to have certain effect in patients with resistance however the benefit is marginal Studies have shown that the union of the tyrosine kinase portion of afatinib in patients with resistance mutation is 100 times less strong that the union in cells with anti-EGFR activating mutations Pre-clinical studies have demonstrated that inhibition of IL-6 receptor activation and activation of JAK1STAT3 pathway overcomes resistance and sensitize again those cells with EGFR resistance mutation
Metformin is a drug that has been used for several years to treat diabetes mellitus and metabolic syndrome its generally well tolerated Several studies since 1910 have suggested that patients with diabetes are at increased risk to develop cancer The American Diabetes Association and The American Cancer Society have come to a consensus that suggests a clear association for greater risk of cancer incidence in diabetic patients The tumors that have been studied with more frequency are in colon endometrium rectus and breast On the other hand several epidemiologic and cases and control studies have suggested that the use of metformin decreases risk to develop cancer up until 30 with a hazard ratio HR of 077 064-092 and risk of cancer-specific death with a HR of 067 053-085 Such protective effect has been seen in all kinds of cancer but has been more studied in breast gastrointestinal and lung cancer
The effect of metformin as chemo-prevention is subject to debate however theres more information about its use as adjuvant in the treatment of lung cancer in combination with chemotherapy or target molecular therapy Pre-clinical studies in mice have demonstrated that use of metformin per os may decrease the necessary dosage of chemotherapy and may prolong tumor remission Metformin by inhibiting repairing and anti-apoptosis mechanisms increases sensitivity to chemotherapy especially to platinum Studies that involve metformin paclitaxel carboplatin and doxorubicin have demonstrated to have an effect in tumor regression and prevention of recurrences up until four times the effect of monotherapy in xenograft models in cellular lines of lung and prostate cancer Retrospective studies have found a benefit in progression-free survival and global survival in diabetic patients with NSCLC who also are treated with metformin
T790M mutation and MET amplification are the main resistance mechanisms to anti-EGFR TKI other mechanisms such as epithelial-mesenchymal transition EMT by TGF-β are resistance mechanisms TGF-β also induces activation of IL-6 and paracrine activation of the receptor IL-6R and at the same time the activation of pathway JAK1STAT3 and cell immortalization Pre-clinical studies with cellular lines of lung cancer with anti-EGFR acquired-resistance treatment show that metformin prevents transcription of factors that activate epithelial-mesenchymal transition inhibiting TGF-β thus inhibiting IL-6JAK1STAT3 pathway overcoming anti-EGFR TKI resistance in patients with T790M resistance mutation in vitro and in vivo A recent study reports that use of metformin in combination with gefitinib may increase efficacy of the latter showing anti-proliferative and pro-apoptotic effect in cellular lines of NSCLC Other studies have shown by Western-blot a decrease in levels of phosphorylation and activation of growth pathways MAPK AKT and mTOR with the use of metformin found in pre-clinical studies Currently a phase III study is being carried out to determine effective dose safety and posteriorly the activity of metformin in combination with erlotinib as second line therapy in patients with NSCLC without EGFR mutation
The main objective of this study is to assess the progression-free survival period in patients with advanced non-small cell lung cancer in treatment with TKIs and metformin versus TKI alone The secondary objectives are the response rate global survival quality of life safety as well as determining the alteration of nutrition parameters associated to the combined use of TKIs and metformin
Besides the secondary objectives we want to find new candidate markers in the tumor characteristics to predict anti-tumor activity as well as the search for serum biomarkers among which we will analyze EGFR mutations exon 18-21 mutations IL-6 IGF-1 as well as determination of LKB-1 molecule expression in tumor tissue We will associate the prognostic and potential role as possible biomarkers
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| Ethics Committe | OTHER | CEI101916 | None |