Ignite Creation Date:
2024-05-06 @ 1:06 AM
Last Modification Date:
2024-10-26 @ 10:59 AM
Study NCT ID:
NCT01726738
Status:
COMPLETED
Last Update Posted:
2020-11-23
First Post:
2012-11-08
Brief Title:
LCCC 1128 Open Label Phase II Trial of the BRAF Inhibitor Dabrafenib and the MEK Inhibitor Trametinib in Unresectable Stage III and Stage IV BRAF Mutant Melanoma Correlation of Resistance With the Kinome and Functional Mutations
Sponsor:
UNC Lineberger Comprehensive Cancer Center
Organization:
UNC Lineberger Comprehensive Cancer Center
Study Overview
Official Title:
LCCC 1128 Open Label Phase II Trial of the BRAF Inhibitor Dabrafenib and the MEK Inhibitor Trametinib in Unresectable Stage III and Stage IV BRAF Mutant Melanoma Correlation of Resistance With the Kinome and Functional Mutations
Status:
COMPLETED
Status Verified Date:
2020-09
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 phase II study in 20 patients with BRAFV600E mutant unresectable stage IIIIV melanoma is designed to explore the mechanisms by which tumors acquire resistance to the combination of a BRAF inhibitor dabrafenib and MEK inhibitor trametinib Tissue will be collected at baseline and at progressionIf a subject is removed from the study for one of a variety of reasons including but not limited to an inability to tolerate the combination of dabrafenib and trametinib a need to receive other therapy or completion of 3-years of study treatment without progression and the subject later receives as part of hisher standard of care the combination of dabrafenib and trametinib and progresses on the standard of care regimen then the subject may be contacted by the treating physician to be put back on to the LCCC 1128 protocol and have a progression biopsy at this progression time point Markers of resistance will be explored by performing near kinome-wide profiling on tumor samples and in patients who co-enroll in institutional protocol LCCC1108 by sequencing tumors using NextGen DNA sequencing technology Overall response rate and duration to this combination will also be assessed
Detailed Description:
The present phase II study in 20 patients with BRAFV600E mutant unresectable stage IIIIV melanoma is designed to explore the mechanisms by which tumors acquire resistance to the combination of BRAF and MEK inhibition Overall response rate and duration to this combination will also be assessed
Tissue will be collected at baseline and at progression clinical or radiological Patients may remain on treatment after progression at the discretion of the investigator as long as they are still experiencing clinical benefit We anticipate that up to 50 of patients may continue on therapy post-progression for 2-8 weeks
BRF113220 the phase III trial of the BRAF inhibitor dabrafenib in combination with the MEK inhibitor trametinib is ongoing in metastatic melanoma to establish the safety of this combination and to determine the recommended phase 2 doses RP2D for each agent Expansion cohorts at the RP2D for these drugs in combination were included in the phase I to characterize the safety in more detail and to explore the efficacy of this combination The combination was well tolerated as described in section 15 with decreased frequency of rash compared to either agent alone and with just 1 report of cutaneous SCC
This proposed study will utilize the RP2D determined in the Phase III study trametinib 2mg QD and dabrafenib 150 mg BID Despite a very promising overall response rate of 81 these patients will also likely go on to develop resistance as a result of new resistance mutations and given the cooperative signaling network of kinases that sense inhibition of key nodal kinases and induce compensatory responses that offset pharmacological intervention The study objectives are as follows Objectives Primary Objective To identify kinases that are differentially expressed pre- and post-treatment with BRAF dabrafenib and MEK trametinib inhibitors and to determine a kinome signature predictive of resistance to BRAFMEK inhibition in stage IIIIV melanoma Secondary Objectives To explore whether resistance to BRAF and MEK inhibition is associated with new functional mutations in the approximately 150 oncogenes tumor suppressor genes that are assessed in more than 10 of the tumors using NextGen DNA sequencing technology in the subset of patients who co-enroll in LCCC1108 with particular focus on one of five established resistance genes BRAF NRAS MEK1 MAP3K8 or COT and PTEN To determine the overall response rate ORR complete response partial response as measured via RECISTv11 To estimate the duration of ORR as measured via RECISTv11 To estimate progression-free survival PFS as defined by RECISTv11 To estimate the rate of overall survival OS at 1 year from day 1 of treatment
Primary Endpoint Kinome signature pathway will be based on comparison of kinome expression from pre- and post-treatment biopsies using Multiplexed Inhibitor Beads MIBs coupled with mass spectrometry
Tissue will be collected at baseline and at progression clinical or radiological Patients may remain on treatment after progression at the discretion of the investigator as long as they are still experiencing clinical benefit We anticipate that up to 50 of patients may continue on therapy post-progression for 2-8 weeks
BRF113220 the phase III trial of the BRAF inhibitor dabrafenib in combination with the MEK inhibitor trametinib is ongoing in metastatic melanoma to establish the safety of this combination and to determine the recommended phase 2 doses RP2D for each agent Expansion cohorts at the RP2D for these drugs in combination were included in the phase I to characterize the safety in more detail and to explore the efficacy of this combination The combination was well tolerated as described in section 15 with decreased frequency of rash compared to either agent alone and with just 1 report of cutaneous SCC
This proposed study will utilize the RP2D determined in the Phase III study trametinib 2mg QD and dabrafenib 150 mg BID Despite a very promising overall response rate of 81 these patients will also likely go on to develop resistance as a result of new resistance mutations and given the cooperative signaling network of kinases that sense inhibition of key nodal kinases and induce compensatory responses that offset pharmacological intervention The study objectives are as follows Objectives Primary Objective To identify kinases that are differentially expressed pre- and post-treatment with BRAF dabrafenib and MEK trametinib inhibitors and to determine a kinome signature predictive of resistance to BRAFMEK inhibition in stage IIIIV melanoma Secondary Objectives To explore whether resistance to BRAF and MEK inhibition is associated with new functional mutations in the approximately 150 oncogenes tumor suppressor genes that are assessed in more than 10 of the tumors using NextGen DNA sequencing technology in the subset of patients who co-enroll in LCCC1108 with particular focus on one of five established resistance genes BRAF NRAS MEK1 MAP3K8 or COT and PTEN To determine the overall response rate ORR complete response partial response as measured via RECISTv11 To estimate the duration of ORR as measured via RECISTv11 To estimate progression-free survival PFS as defined by RECISTv11 To estimate the rate of overall survival OS at 1 year from day 1 of treatment
Primary Endpoint Kinome signature pathway will be based on comparison of kinome expression from pre- and post-treatment biopsies using Multiplexed Inhibitor Beads MIBs coupled with mass spectrometry
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