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
The present phase II study in 20 patients with BRAFV600E mutant, unresectable stage III/IV
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 I/II 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 1.5, 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 I/II 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
BRAF/MEK inhibition in stage III/IV 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 RECISTv1.1 To estimate the duration of ORR as
measured via RECISTv1.1 To estimate progression-free survival (PFS) as defined by RECISTv1.1
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
Endpoint Classification: Pharmacodynamics Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
The primary outcome of this study is to identify kinases that are differentially expressed pre- and post-treatment with BRAF (dabrafenib) and MEK (trametinib) inhibitors. The kinases will be profiled using Multiplexed Inhibitor Beads (MIBs) coupled with mass spectrometry.
One year post treatment
Frances Collichio, MD
UNC Lineberger Comprehensive Cancer Center
United States: Food and Drug Administration
|Lineberger Comprehensive Cancer Center, University of North Carolina||Chapel Hill, North Carolina 27599|