Ignite Creation Date:
2024-05-06 @ 7:47 AM
Last Modification Date:
2024-10-26 @ 11:52 AM
Study NCT ID:
NCT02609958
Status:
COMPLETED
Last Update Posted:
2018-05-29
First Post:
2015-11-08
Brief Title:
ASLAN001 in Patients With Advanced or Metastatic Cholangiocarcinoma Who Progressed on at Least 1 Line of Systemic Therapy
Sponsor:
ASLAN Pharmaceuticals
Organization:
ASLAN Pharmaceuticals
Study Overview
Official Title:
A Phase 2A Single Arm Multicentre Study of ASLAN001 in Patients With Advanced or Metastatic Cholangiocarcinoma Who Progressed on at Least 1 Line of Systemic Therapy
Status:
COMPLETED
Status Verified Date:
2018-05
Last Known Status:
None
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:
This is a single arm multicentre Phase 2 study to assess efficacy and safety of ASLAN001 in patients with advanced or metastatic cholangiocarcinoma who progressed on at least 1 line of systemic therapy
25 evaluable patients will be enrolled in the study After evaluation of initial response in the first 10 evaluable patients Sponsor will make a decision on recruitment of an additional 15 evaluable patients If no response is observed the study will stop
The primary objective is to assess efficacy of varlitinib also known as ASLAN001 as measured by ORR based on RECIST v11 The secondary objectives are to 1 evaluate the efficacy of varlitinib as measured by DoR PFS OS and DCR 2 assess ORR DoR PFS DCR and OS by tumor EGFRHER2 status 3 assess safety and tolerability of ASLAN001 monotherapy Exploratory objectives are to explore possible relationships between response to ASLAN001 and the protein expression levels and gene mutational status of the proteins and genes via IHC and PCRSequencing
25 evaluable patients will be enrolled in the study After evaluation of initial response in the first 10 evaluable patients Sponsor will make a decision on recruitment of an additional 15 evaluable patients If no response is observed the study will stop
The primary objective is to assess efficacy of varlitinib also known as ASLAN001 as measured by ORR based on RECIST v11 The secondary objectives are to 1 evaluate the efficacy of varlitinib as measured by DoR PFS OS and DCR 2 assess ORR DoR PFS DCR and OS by tumor EGFRHER2 status 3 assess safety and tolerability of ASLAN001 monotherapy Exploratory objectives are to explore possible relationships between response to ASLAN001 and the protein expression levels and gene mutational status of the proteins and genes via IHC and PCRSequencing
Detailed Description:
Cholangiocarcinoma CCA is a malignancy arising from the biliary epithelium characterized by poor prognosis and poor response to current treatments Emerging at any portion of the biliary tree it includes a group of tumours with epidemiologic morphologic biologic and clinical heterogeneity Despite recent medical advances the long-term outcomes and recurrence rates for CCA are poor The 5-year survival rate following surgical resection is 11-40 Tumour recurrence rates are as high as 50-65 with a median time to recurrence between 12-43 months
In the United States the incidence and mortality of CCA have increased over the last 30 years without clear underlying etiological reasons The only curative therapy is surgical however this is not an option for many patients given the stage of the disease at presentation and metastasis While improvements in diagnostic modalities and neoadjuvant chemotherapy have allowed for detection at earlier stages and greater survival rates the prognosis is still unfavorable Therapies that can decrease tumour growth improve resection outcomes increase survival rates and decrease recurrence would make a great impact on the quality of life of CCA patients and are urgently needed
Currently the Food and Drug Administration FDA-approved agents used in unresectable CCA include gemcitabine capecitabine cisplatin oxaliplatin fluoropyrimidines including 5-fluorouracil or a combination of these However none are FDA-approved primarily for use in CCA specifically Gemcitabine and cisplatin combination therapy along with fluoropyrimidine-based or other gemcitabine-based regimens are part of the guidelines for unresectable cancer per the National Comprehensive Cancer Network To date the most effective chemotherapy regimen is administration of gemcitabine with cisplatin or oxaliplatin which have now become the standard of care for systemic therapy Even this most efficacious treatment has been found to only modestly increase overall survival 117 months vs 83 months for patients receiving gemcitabine alone and progression-free survival 84 vs 65 months Standard treatment as second-line chemotherapy for CCA is unclear as there is no significant evidence for specific therapy which indicates that further chemotherapy beyond progression on first-line chemotherapy improves survival
CCA involves mutations in members of the ErbB family including EGFR and HER2 mutations EGFR is overexpressed in both intrahepatic and extrahepatic CCA 308 and 209 respectively and is an independent prognostic factor in intrahepatic cases per Yang et al 2014 While this study found overexpression of HER2 exclusively in extrahepatic samples and only in 45 of these previous studies have implicated this protein in both extra- and intrahepatic tumours Settakorn et al 2005 showed HER2 expression is correlated with high histological grade in intrahepatic CCA Kim et al 2007 found HER2 gene and protein levels are overexpressed in approximately 30 of extrahepatic CCA patients and is a prognostic factor for survival in those with lymph node metastasis
EGFR HER2 and HER4 are single-pass transmembrane glycoprotein receptors members of the type I receptor tyrosine kinase family Upon ligand binding their activation induces the homo- or heterodimerization and subsequent phosphorylation of intracellular tyrosines which lead to both cell proliferation and survival and therefore cancer development and progression EGFR and HER2 inhibitors have both demonstrated clinical efficacy in cancer treatment The simultaneous inhibition of both represents a new therapeutic approach for broadly targeting different tumour types that may be more effective than selective inhibition of each receptor
Varlitinib also known as ASLAN001 is a potent orally active inhibitor of the receptor tyrosine kinases epidermal growth factor EGFR and human epidermal growth factor receptors 2 and 4 HER2 HER4 In cell-based assays varlitinib has been shown to potently inhibit the phosphorylation of EGFR HER2 and HER4 in a dose-dependent manner In cell lines overexpressing HER2 varlitinib also inhibited the phosphorylation of the HER2 downstream effector AKT
ASLAN hypothesises that varlitinib will inhibit EGFR HER2 HER4 as their mutations results in CCA thus in turn inhibiting the growth of cancerous cells and developmentprogression ASLAN believes that varlitinib is a compound that may be beneficial to patients with cancer by simultaneous inhibition of these receptors
In the United States the incidence and mortality of CCA have increased over the last 30 years without clear underlying etiological reasons The only curative therapy is surgical however this is not an option for many patients given the stage of the disease at presentation and metastasis While improvements in diagnostic modalities and neoadjuvant chemotherapy have allowed for detection at earlier stages and greater survival rates the prognosis is still unfavorable Therapies that can decrease tumour growth improve resection outcomes increase survival rates and decrease recurrence would make a great impact on the quality of life of CCA patients and are urgently needed
Currently the Food and Drug Administration FDA-approved agents used in unresectable CCA include gemcitabine capecitabine cisplatin oxaliplatin fluoropyrimidines including 5-fluorouracil or a combination of these However none are FDA-approved primarily for use in CCA specifically Gemcitabine and cisplatin combination therapy along with fluoropyrimidine-based or other gemcitabine-based regimens are part of the guidelines for unresectable cancer per the National Comprehensive Cancer Network To date the most effective chemotherapy regimen is administration of gemcitabine with cisplatin or oxaliplatin which have now become the standard of care for systemic therapy Even this most efficacious treatment has been found to only modestly increase overall survival 117 months vs 83 months for patients receiving gemcitabine alone and progression-free survival 84 vs 65 months Standard treatment as second-line chemotherapy for CCA is unclear as there is no significant evidence for specific therapy which indicates that further chemotherapy beyond progression on first-line chemotherapy improves survival
CCA involves mutations in members of the ErbB family including EGFR and HER2 mutations EGFR is overexpressed in both intrahepatic and extrahepatic CCA 308 and 209 respectively and is an independent prognostic factor in intrahepatic cases per Yang et al 2014 While this study found overexpression of HER2 exclusively in extrahepatic samples and only in 45 of these previous studies have implicated this protein in both extra- and intrahepatic tumours Settakorn et al 2005 showed HER2 expression is correlated with high histological grade in intrahepatic CCA Kim et al 2007 found HER2 gene and protein levels are overexpressed in approximately 30 of extrahepatic CCA patients and is a prognostic factor for survival in those with lymph node metastasis
EGFR HER2 and HER4 are single-pass transmembrane glycoprotein receptors members of the type I receptor tyrosine kinase family Upon ligand binding their activation induces the homo- or heterodimerization and subsequent phosphorylation of intracellular tyrosines which lead to both cell proliferation and survival and therefore cancer development and progression EGFR and HER2 inhibitors have both demonstrated clinical efficacy in cancer treatment The simultaneous inhibition of both represents a new therapeutic approach for broadly targeting different tumour types that may be more effective than selective inhibition of each receptor
Varlitinib also known as ASLAN001 is a potent orally active inhibitor of the receptor tyrosine kinases epidermal growth factor EGFR and human epidermal growth factor receptors 2 and 4 HER2 HER4 In cell-based assays varlitinib has been shown to potently inhibit the phosphorylation of EGFR HER2 and HER4 in a dose-dependent manner In cell lines overexpressing HER2 varlitinib also inhibited the phosphorylation of the HER2 downstream effector AKT
ASLAN hypothesises that varlitinib will inhibit EGFR HER2 HER4 as their mutations results in CCA thus in turn inhibiting the growth of cancerous cells and developmentprogression ASLAN believes that varlitinib is a compound that may be beneficial to patients with cancer by simultaneous inhibition of these receptors
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