Ignite Creation Date:
2024-10-26 @ 3:40 PM
Last Modification Date:
2024-10-26 @ 3:40 PM
Study NCT ID:
NCT06592989
Status:
NOT_YET_RECRUITING
Last Update Posted:
None
First Post:
2024-09-08
Brief Title:
A Clinical Study of Sorafenib Combined With Gefitinib for the Treatment of pNET
Sponsor:
None
Organization:
None
Study Overview
Official Title:
A Clinical Study of Sorafenib Combined With Gefitinib for the Treatment of Pancreatic Neuroendocrine Tumor Patients Who Have Progressed After Previous Treatment
Status:
NOT_YET_RECRUITING
Status Verified Date:
2024-09
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
No
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
The incidence rate of pancreatic neuroendocrine neoplasms pNENs is increasing year by year According to the statistical results of the SEER Surveillance Epidemiology and End Results database the incidence rate of pNENs increased from 027100000 to 1100000 from 2000 to 2016 with a median overall survival time of 68 months The 5-year overall survival rates of localized locally advanced and metastatic pNENs were 83 67 and 28 respectively pNENs are gradually gaining attention and importance from the medical community The existing therapeutic drugs for neuroendocrine tumors include somatostatin analogues recombinant human interferon injections chemotherapy drugs and molecular targeted drugs
Although these drugs can prolong patients PFS to some extent there is a common problem of low objective response rates In recent years sunitinib and everolimus have been approved for targeted therapy in patients with pancreatic neuroendocrine neoplasms but their clinical efficacy is still limited The study by Panzuto et al showed that the median PFS for first-line treatment of advanced well differentiated pancreatic neuroendocrine neoplasms was 139 months with an ORR of 149 After imaging progression of the disease the median PFS after second-line treatment was 15 months and the ORR of only 55 There is currently no effective treatment for patients with disease progression or drug resistance after undergoing existing treatment ways
Therefore there is a huge clinical demand for the treatment of pNEN patients worldwide and effective drugs are urgently needed to benefit these patients
Our previous research found that pathways in tumor were significantly affected in pNENs and liver metastases and EGFR tyrosine kinase inhibitor resistance and transcriptional dysregulation in tumor were unique to liver metastasis through KEGG pathway analysis Meanwhile GO Biological Processes analysis emphasizes those signaling pathways closely related to tyrosine phosphorylation DNA repair and cell cycle regulation especially in liver metastases Xiao et al found that epidermal growth factor receptor EGFR was enriched in high glycosylation pNENs using RNA-seq EGFR was expressed in 212 of pNENs using immunohistochemistry and associated with poor overall survival Therefore the study from Xiao et al demonstrates that EGFR may be a potential therapeutic target for pNENs This is consistent with our previous findings that the EGFR signaling pathway plays an important role in pNENs with liver metastases
Due to the heterogeneity and complexity of tumors the efficacy of monotherapy or blocking a single signaling pathway may be limited or this treatment method may easily develop drug resistance The existing anti-tumor targeted drugs block tumor angiogenesis by inhibiting vascular endothelial growth factor VEGF and fibroblast growth factor FGF Colony-stimulating factor 1 receptor CSF1R is an important signaling pathway associated with the survival and function of tumor associated macrophages TAMs Inhibiting CSF1R can regulate the activity of macrophages improve the immune microenvironment promote immune response and activate the bodys immune function Sofantinib is a novel oral tyrosine kinase inhibitor which exerts dual effects of anti-tumor angiogenesis and immune regulation by targeting VEGFR FGFR1 and CSF1R resulting in synergistic anti-tumor activity In December 2020 and June 2021 sorafenib was approved in China as a monotherapy for unresectable locally advanced or metastatic well differentiated extrapancreatic and pancreatic neuroendocrine neoplasms
However in a multicenter single blind open label phase IbII clinical trial the objective response rate for pNENs patients was only 19 There is currently no effective treatment available for patients with disease progression or drug resistance after undergoing existing treatment regimens Therefore there is an urgent need to seek new treatment methods to improve the therapeutic effect of pNENs Based on our previous research results and relevant literature reports we speculate that the combination of sorafenib and EGFR inhibitor gefitinib may improve the therapeutic effect of pNENs patients
Although these drugs can prolong patients PFS to some extent there is a common problem of low objective response rates In recent years sunitinib and everolimus have been approved for targeted therapy in patients with pancreatic neuroendocrine neoplasms but their clinical efficacy is still limited The study by Panzuto et al showed that the median PFS for first-line treatment of advanced well differentiated pancreatic neuroendocrine neoplasms was 139 months with an ORR of 149 After imaging progression of the disease the median PFS after second-line treatment was 15 months and the ORR of only 55 There is currently no effective treatment for patients with disease progression or drug resistance after undergoing existing treatment ways
Therefore there is a huge clinical demand for the treatment of pNEN patients worldwide and effective drugs are urgently needed to benefit these patients
Our previous research found that pathways in tumor were significantly affected in pNENs and liver metastases and EGFR tyrosine kinase inhibitor resistance and transcriptional dysregulation in tumor were unique to liver metastasis through KEGG pathway analysis Meanwhile GO Biological Processes analysis emphasizes those signaling pathways closely related to tyrosine phosphorylation DNA repair and cell cycle regulation especially in liver metastases Xiao et al found that epidermal growth factor receptor EGFR was enriched in high glycosylation pNENs using RNA-seq EGFR was expressed in 212 of pNENs using immunohistochemistry and associated with poor overall survival Therefore the study from Xiao et al demonstrates that EGFR may be a potential therapeutic target for pNENs This is consistent with our previous findings that the EGFR signaling pathway plays an important role in pNENs with liver metastases
Due to the heterogeneity and complexity of tumors the efficacy of monotherapy or blocking a single signaling pathway may be limited or this treatment method may easily develop drug resistance The existing anti-tumor targeted drugs block tumor angiogenesis by inhibiting vascular endothelial growth factor VEGF and fibroblast growth factor FGF Colony-stimulating factor 1 receptor CSF1R is an important signaling pathway associated with the survival and function of tumor associated macrophages TAMs Inhibiting CSF1R can regulate the activity of macrophages improve the immune microenvironment promote immune response and activate the bodys immune function Sofantinib is a novel oral tyrosine kinase inhibitor which exerts dual effects of anti-tumor angiogenesis and immune regulation by targeting VEGFR FGFR1 and CSF1R resulting in synergistic anti-tumor activity In December 2020 and June 2021 sorafenib was approved in China as a monotherapy for unresectable locally advanced or metastatic well differentiated extrapancreatic and pancreatic neuroendocrine neoplasms
However in a multicenter single blind open label phase IbII clinical trial the objective response rate for pNENs patients was only 19 There is currently no effective treatment available for patients with disease progression or drug resistance after undergoing existing treatment regimens Therefore there is an urgent need to seek new treatment methods to improve the therapeutic effect of pNENs Based on our previous research results and relevant literature reports we speculate that the combination of sorafenib and EGFR inhibitor gefitinib may improve the therapeutic effect of pNENs patients
Detailed Description:
Neuroendocrine neoplasms NENs are heterogeneous tumors originating from peptidogenic neurons and neuroendocrine cells Most commonly found in the digestive tract or lungs it can be a benign or malignant tumor According to their origin neuroendocrine neoplasms are usually divided into pancreatic neuroendocrine neoplasms and non pancreatic neuroendocrine neoplasms Approved targeted therapy drugs include sunitinib and everolimus used to treat pancreatic neuroendocrine neoplasms or highly differentiated non functional gastrointestinal or pulmonary neuroendocrine neoplasms The gastrointestinal tract and pancreas are home to 12 and 4 types of neuroendocrine cells respectively and are the most common sites of NEN occurrence accounting for approximately 55 to 70 of all NENs The incidence rate of neuroendocrine neoplasms from gastrointestinal tract and pancreas is about 525100000 which is the second common tumor of gastrointestinal tract In China the ratio of incidence rate and prevalence of neuroendocrine neoplasms is estimated to be 44 lower than 74 in the United States
In 2018 there were 19000 newly diagnosed cases of neuroendocrine neoplasms in the United States It is noteworthy that compared with other tumors the survival period of patients with neuroendocrine neoplasms is relatively long Therefore although the incidence rate of neuroendocrine neoplasms is relatively low the patient population is relatively large In addition it is estimated that there were approximately 141000 neuroendocrine neoplasm patients in the United States in 2018 of which over 90 or 132000 patients were non pancreatic neuroendocrine neoplasm patients In China there were approximately 67600 newly diagnosed cases of neuroendocrine neoplasms in 2018 According to Chinas incidence to prevalence ratio there may be as many as 300000 patients with neuroendocrine neoplasms in China It is estimated that about 80 of patients with neuroendocrine neoplasms in China are non pancreatic neuroendocrine neoplasm patients Octreotide and Lancreotide which belong to Somatostatin Analogues SSAs can alleviate symptoms such as flushing and diarrhea caused by carcinoid syndrome and have been widely used in clinical practice In a phase III clinical study comparing long-acting octreotide LAR with placebo in the treatment of 85 cases of metastatic colorectal cancer NENs PROMID octreotide LAR significantly prolonged the time to disease progression TTP in patients Octreotide LAR group at 143 months and placebo group at 6 months p0000072 A systematic analysis report shows that after combination therapy with long-acting octreotide and other therapies including everolimus peptide receptor radionuclide therapy bevacizumab interferon etc 85 of patients diseases were controlled with PFS ranging from 15 months to 164 months and OS ranging from 25 months to 619 months SSAs are well tolerated drugs with few side effects usually mild and do not require discontinuation5
The incidence rate of pancreatic neuroendocrine neoplasms pNENs is increasing year by year According to the statistical results of the Surveillance Epidemiology and End Results SEER database the incidence rate of pNENs increased from 027100000 to 1100000 from 2000 to 2016 with a median overall survival time of 68 months and the 5-year overall survival rates OS of localized locally advanced and metastatic pNENs were 83 67 and 28 respectively pNENs are gradually attracting attention and importance from the medical community The existing therapeutic drugs for neuroendocrine neoplasms include growth hormone inhibitors recombinant human interferon injections chemotherapy drugs and molecular targeted drugs Although these drugs can to some extent prolong patients PFS there is a common problem of low objective response rates In recent years sunitinib and everolimus have been approved for targeted therapy in patients with pancreatic neuroendocrine tumors but their clinical efficacy is still limited The study from Panzuto et al showed that the median PFS for first-line treatment of advanced well differentiated pancreatic neuroendocrine neoplasms was 139 months with an ORR of 149 When imaging progression occurred and second-line treatment was adopted the median PFS after second-line treatment was 15 months with an ORR of only 55 There is currently no effective treatment for patients with disease progression or drug resistance after existing treatments
Therefore there is a huge clinical demand for the treatment of pancreatic neuroendocrine neoplasm patients both domestically and globally and effective drugs are urgently needed to benefit the vast number of patients
Our previous research found that tumor signaling pathways are significantly affected in pancreatic neuroendocrine neoplasms and liver metastasis through KEGG pathway analysis EGFR tyrosine kinase inhibitor resistance and transcriptional dysregulation in tumors are unique to liver metastasis Meanwhile GO biological process analysis emphasizes signaling pathways closely related to tyrosine phosphorylation DNA repair and cell cycle regulation Xiao et al found that RNA seq was used to enrich epidermal growth factor receptor EGFR in high glycosylated pancreatic neuroendocrine neoplasms Immunohistochemical staining revealed that 212 of pancreatic neuroendocrine tumors expressed EGFR which was associated with low overall survival rate P0020 Therefore Xiao et al believe that EGFR may be a potential therapeutic target for pancreatic neuroendocrine neoplasms This is consistent with our previous findings that the EGFR signaling pathway plays an important role in pancreatic neuroendocrine neoplasms with liver metastasis
Due to the heterogeneity and complexity of tumors the efficacy of monotherapy or blocking a single signaling pathway may be limited The existing targeted anti-tumor drugs block tumor angiogenesis by inhibiting vascular endothelial growth factor VEGF and fibroblast growth factor FGF Colony stimulating factor 1 receptor CSF1R is an important signaling pathway associated with the survival and function of tumor associated macrophages TAMs Inhibiting CSF1R can regulate the activity of macrophages improve the immune microenvironment promote immune response in the body and activate immune function Sofantinib is a novel oral tyrosine kinase inhibitor that exerts dual effects of anti angiogenesis and immune regulation by targeting vascular endothelial growth factor receptor VEGFR fibroblast growth factor receptor FGFR1 and colony-stimulating factor 1 receptor CSF1R kinases resulting in synergistic anti-tumor activity In December 2020 and June 2021 sorafenib was approved in China as a monotherapy for unresectable locally advanced or metastatic well differentiated extrapancreatic and pancreatic neuroendocrine neoplasms However in a multicenter single blind open label phase IbII clinical trial the objective response rate for pancreatic neuroendocrine tumor patients was only 19 and there is no effective treatment for patients with disease progression or drug resistance after existing treatment regimens Therefore there is an urgent need to seek new treatment methods to improve the therapeutic effect of pancreatic neuroendocrine neoplasms
There is a study showing that dual inhibition of epidermal growth factor receptor and vascular endothelial growth factor pathways may delay therapeutic resistance in advanced non-small cell lung cancer NSCLC Bevacizumab plus erlotinib significantly improved PFS in patients with untreated metastatic EGFR-mutated NSCLC Based on previous research results and relevant literature reports we speculate that the combination of sorafenib and EGFR inhibitors gefitinib may improve the treatment efficacy of patients
In 2018 there were 19000 newly diagnosed cases of neuroendocrine neoplasms in the United States It is noteworthy that compared with other tumors the survival period of patients with neuroendocrine neoplasms is relatively long Therefore although the incidence rate of neuroendocrine neoplasms is relatively low the patient population is relatively large In addition it is estimated that there were approximately 141000 neuroendocrine neoplasm patients in the United States in 2018 of which over 90 or 132000 patients were non pancreatic neuroendocrine neoplasm patients In China there were approximately 67600 newly diagnosed cases of neuroendocrine neoplasms in 2018 According to Chinas incidence to prevalence ratio there may be as many as 300000 patients with neuroendocrine neoplasms in China It is estimated that about 80 of patients with neuroendocrine neoplasms in China are non pancreatic neuroendocrine neoplasm patients Octreotide and Lancreotide which belong to Somatostatin Analogues SSAs can alleviate symptoms such as flushing and diarrhea caused by carcinoid syndrome and have been widely used in clinical practice In a phase III clinical study comparing long-acting octreotide LAR with placebo in the treatment of 85 cases of metastatic colorectal cancer NENs PROMID octreotide LAR significantly prolonged the time to disease progression TTP in patients Octreotide LAR group at 143 months and placebo group at 6 months p0000072 A systematic analysis report shows that after combination therapy with long-acting octreotide and other therapies including everolimus peptide receptor radionuclide therapy bevacizumab interferon etc 85 of patients diseases were controlled with PFS ranging from 15 months to 164 months and OS ranging from 25 months to 619 months SSAs are well tolerated drugs with few side effects usually mild and do not require discontinuation5
The incidence rate of pancreatic neuroendocrine neoplasms pNENs is increasing year by year According to the statistical results of the Surveillance Epidemiology and End Results SEER database the incidence rate of pNENs increased from 027100000 to 1100000 from 2000 to 2016 with a median overall survival time of 68 months and the 5-year overall survival rates OS of localized locally advanced and metastatic pNENs were 83 67 and 28 respectively pNENs are gradually attracting attention and importance from the medical community The existing therapeutic drugs for neuroendocrine neoplasms include growth hormone inhibitors recombinant human interferon injections chemotherapy drugs and molecular targeted drugs Although these drugs can to some extent prolong patients PFS there is a common problem of low objective response rates In recent years sunitinib and everolimus have been approved for targeted therapy in patients with pancreatic neuroendocrine tumors but their clinical efficacy is still limited The study from Panzuto et al showed that the median PFS for first-line treatment of advanced well differentiated pancreatic neuroendocrine neoplasms was 139 months with an ORR of 149 When imaging progression occurred and second-line treatment was adopted the median PFS after second-line treatment was 15 months with an ORR of only 55 There is currently no effective treatment for patients with disease progression or drug resistance after existing treatments
Therefore there is a huge clinical demand for the treatment of pancreatic neuroendocrine neoplasm patients both domestically and globally and effective drugs are urgently needed to benefit the vast number of patients
Our previous research found that tumor signaling pathways are significantly affected in pancreatic neuroendocrine neoplasms and liver metastasis through KEGG pathway analysis EGFR tyrosine kinase inhibitor resistance and transcriptional dysregulation in tumors are unique to liver metastasis Meanwhile GO biological process analysis emphasizes signaling pathways closely related to tyrosine phosphorylation DNA repair and cell cycle regulation Xiao et al found that RNA seq was used to enrich epidermal growth factor receptor EGFR in high glycosylated pancreatic neuroendocrine neoplasms Immunohistochemical staining revealed that 212 of pancreatic neuroendocrine tumors expressed EGFR which was associated with low overall survival rate P0020 Therefore Xiao et al believe that EGFR may be a potential therapeutic target for pancreatic neuroendocrine neoplasms This is consistent with our previous findings that the EGFR signaling pathway plays an important role in pancreatic neuroendocrine neoplasms with liver metastasis
Due to the heterogeneity and complexity of tumors the efficacy of monotherapy or blocking a single signaling pathway may be limited The existing targeted anti-tumor drugs block tumor angiogenesis by inhibiting vascular endothelial growth factor VEGF and fibroblast growth factor FGF Colony stimulating factor 1 receptor CSF1R is an important signaling pathway associated with the survival and function of tumor associated macrophages TAMs Inhibiting CSF1R can regulate the activity of macrophages improve the immune microenvironment promote immune response in the body and activate immune function Sofantinib is a novel oral tyrosine kinase inhibitor that exerts dual effects of anti angiogenesis and immune regulation by targeting vascular endothelial growth factor receptor VEGFR fibroblast growth factor receptor FGFR1 and colony-stimulating factor 1 receptor CSF1R kinases resulting in synergistic anti-tumor activity In December 2020 and June 2021 sorafenib was approved in China as a monotherapy for unresectable locally advanced or metastatic well differentiated extrapancreatic and pancreatic neuroendocrine neoplasms However in a multicenter single blind open label phase IbII clinical trial the objective response rate for pancreatic neuroendocrine tumor patients was only 19 and there is no effective treatment for patients with disease progression or drug resistance after existing treatment regimens Therefore there is an urgent need to seek new treatment methods to improve the therapeutic effect of pancreatic neuroendocrine neoplasms
There is a study showing that dual inhibition of epidermal growth factor receptor and vascular endothelial growth factor pathways may delay therapeutic resistance in advanced non-small cell lung cancer NSCLC Bevacizumab plus erlotinib significantly improved PFS in patients with untreated metastatic EGFR-mutated NSCLC Based on previous research results and relevant literature reports we speculate that the combination of sorafenib and EGFR inhibitors gefitinib may improve the treatment efficacy of patients
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