Ignite Creation Date:
2024-05-06 @ 10:19 AM
Last Modification Date:
2024-10-26 @ 12:28 PM
Study NCT ID:
NCT03224208
Status:
TERMINATED
Last Update Posted:
2021-04-26
First Post:
2017-07-19
Brief Title:
Vemurafenib Plus Cobimetinib in Advanced or Metastatic Melanoma Patients
Sponsor:
Fondazione Melanoma Onlus
Organization:
Fondazione Melanoma Onlus
Study Overview
Official Title:
VECODUE A Phase II Trial of Vemurafenib Plus Cobimetinib in Patients Treated With Prior First-line Systemic Immunotherapy for Inoperable Locally Advanced or Metastatic Melanoma
Status:
TERMINATED
Status Verified Date:
2021-04
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
low enrolment rate
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
VECODUE
Brief Summary:
In the BRIM-3 trial which was conducted in patients with previously untreated advanced melanoma harboring the BRAF V600E mutation vemurafenib a potent inhibitor of mutated BRAF was associated with prolonged overall survival OS and progression-free survival PFS compared to dacarbazine In the same setting combined use of vemurafenib and cobimetinib a selective inhibitor of MEK yielded a significant improvement in PFS and response rate compared to vemurafenib monotherapy along with an advantage in OS which did not cross the pre-specified significance bounderies COBRIM trial In treatment-naïve patients with mutated BRAF both anti PD-1-based immunotherapy and BRAF-targeted agents are feasible therapeutic options with the former and latter agents being associated with more durable and earlier responses respectively
As suggested by National Comprehensive Cancer Network NCCN guidelines the use of combined BRAF and MEK inhibitors in patients with progressive disease after immunotherapy is also feasible but it is not supported by category 1 evidence in view of the lack of studies conducted in this setting
The main objective of this phase II trial is to evaluate the efficacy and safety of the combined use of vemurafenib plus cobimetinib in advanced melanoma patients who have received first-line systemic immunotherapy for inoperable locally advanced metastatic disease
As suggested by National Comprehensive Cancer Network NCCN guidelines the use of combined BRAF and MEK inhibitors in patients with progressive disease after immunotherapy is also feasible but it is not supported by category 1 evidence in view of the lack of studies conducted in this setting
The main objective of this phase II trial is to evaluate the efficacy and safety of the combined use of vemurafenib plus cobimetinib in advanced melanoma patients who have received first-line systemic immunotherapy for inoperable locally advanced metastatic disease
Detailed Description:
In the BRIM-3 trial which was conducted in patients with previously untreated advanced melanoma harboring the BRAF V600E mutation vemurafenib a potent inhibitor of mutated BRAF was associated with prolonged OS and PFS compared to dacarbazine In the same setting combined use of vemurafenib and cobimetinib a selective inhibitor of MEK yielded a significant improvement in PFS and response rate compared to vemurafenib monotherapy along with an advantage in OS which did not cross the pre-specified significance bounderies COBRIM trial In treatment-naïve patients with mutated BRAF both anti PD-1-based immunotherapy and BRAF-targeted agents are feasible therapeutic options with the former and latter agents being associated with more durable and earlier responses respectively
As suggested by NCCN guidelines the use of combined BRAF and MEK inhibitors in patients with progressive disease after immunotherapy is also feasible but it is not supported by category 1 evidence in view of the lack of studies conducted in this setting
The main objective of this phase II trial is to evaluate the efficacy and safety of the combined use of vemurafenib plus cobimetinib in advanced melanoma patients who have received first-line systemic immunotherapy for inoperable locally advanced metastatic disease
As evidenced above vemurafenib inhibits the BRAF V600E kinase this mutation is found in 50 to 60 of melanomas and enables a remarkable clinical response rate more than 50 and a statistically significant improvement in OS in patients with unresectable stage III and IV melanoma
However the clinical utility of BRAF-I treatment is limited by the development of drug resistance Multiple mechanisms underlie the development of BRAF-I resistance in BRAF V600E melanoma cells including point mutations in MEK1 amplification of mutant BRAF V600E elevated closely related serinethreonine kinase activity activating NRAS mutations increased levels of COTTpl2 aberrantly spliced BRAF V600E and growth factor receptor upregulation Most of these alterations cause BRAF-I resistance by reactivating the MAPK pathway which plays a major role in the proliferation survival and metastatic potential of melanoma cells Shi 2014a Shi 2014b Van Allen 2014
Inhibition of MEK by the novel MEK-I trametenib or cobimetinib has been demonstrated to overcome the reactivation of MAPK pathway which is induced by BRAF-I resistance and to increase both OS and OvRR of melanoma patients when combined with BRAF-I Flaherty 2012a Flaherty 2012b Hoeflich 2012 Ribas 2014 The above-described phase III study 495 patients with previously untreated unresectable locally advanced or metastatic BRAF V600 mutation-positive melanoma has shown that the combination of vemurafenib and cobimetinib as compared with vemurafenib alone resulted in an improvement in PFS and objective responses with early evidence of improved OS and a somewhat increased toxicity profile Larkin 2014
As suggested by NCCN guidelines the use of combined BRAF and MEK inhibitors in patients with progressive disease after immunotherapy is also feasible but it is not supported by category 1 evidence in view of the lack of studies conducted in this setting
The main objective of this phase II trial is to evaluate the efficacy and safety of the combined use of vemurafenib plus cobimetinib in advanced melanoma patients who have received first-line systemic immunotherapy for inoperable locally advanced metastatic disease
As evidenced above vemurafenib inhibits the BRAF V600E kinase this mutation is found in 50 to 60 of melanomas and enables a remarkable clinical response rate more than 50 and a statistically significant improvement in OS in patients with unresectable stage III and IV melanoma
However the clinical utility of BRAF-I treatment is limited by the development of drug resistance Multiple mechanisms underlie the development of BRAF-I resistance in BRAF V600E melanoma cells including point mutations in MEK1 amplification of mutant BRAF V600E elevated closely related serinethreonine kinase activity activating NRAS mutations increased levels of COTTpl2 aberrantly spliced BRAF V600E and growth factor receptor upregulation Most of these alterations cause BRAF-I resistance by reactivating the MAPK pathway which plays a major role in the proliferation survival and metastatic potential of melanoma cells Shi 2014a Shi 2014b Van Allen 2014
Inhibition of MEK by the novel MEK-I trametenib or cobimetinib has been demonstrated to overcome the reactivation of MAPK pathway which is induced by BRAF-I resistance and to increase both OS and OvRR of melanoma patients when combined with BRAF-I Flaherty 2012a Flaherty 2012b Hoeflich 2012 Ribas 2014 The above-described phase III study 495 patients with previously untreated unresectable locally advanced or metastatic BRAF V600 mutation-positive melanoma has shown that the combination of vemurafenib and cobimetinib as compared with vemurafenib alone resulted in an improvement in PFS and objective responses with early evidence of improved OS and a somewhat increased toxicity profile Larkin 2014
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