This is a Phase 2 trial consisting of 24 patients receiving the combination of dabrafenib + trametinib + pembrolizumab in 3 different dosing schemes and 8 patients receiving pembrolizumab standard monotherapy. All patients start with pembrolizumab standard therapy for 6 weeks and will then be randomized to continue pembrolizumab monotherapy or to receive additional intermitted/short-term dabrafenib + trametinib. Stratification will be baseline LDH level and baseline PD-L1 expression.
Name: Pembrolizumab
Name: Dabrafenib
Name: Trametinib
Name: Biopsy
Name: Blood taking
Description: Safety as measured by SUSARs during treatment week 0 till week 18.
Measure: Safety of different schemes of continuous/intermittent dabrafenib+trametinib during treatment with pembrolizumab as compared to pembrolizumab monotherapy as measured by SUSARs. Time: 18 weeks from baselineDescription: Feasibility as measured by adherence to the timelines in the study protocol (week 0 till week 18).
Measure: Feasibility of different schemes of continuous/intermittent dabrafenib+trametinib during treatment with pembrolizumab as compared to pembrolizumab monotherapy as measured by adherence to the timelines in the study protocol. Time: 18 weeks from baseline.Description: Readout will be the alterations in magnitude or breadth of the self-antigen specific T cell responses in the time interval pre-treatment to week 18 intrapatient, and interpatient, pembrolizumab only (cohort 1) versus pembrolizumab plus intermittent dabrafenib/ trametinib (cohorts 2-4). To this purpose, we will analyze melanoma antigen-specific T cells responses by HLA-A2-restricted MHC-tetramer staining.
Measure: The immune-activating capacity of different schemes of continuous/intermittent dabrafenib+trametinib during treatment with pembrolizumab as compared to pembrolizumab monotherapy Time: 18 weeks from baseline.Description: Rates of response at week 6, week 12, week 18 according to RECIST 1.1 criteria
Measure: To determine rates of response at week 6, 12, week 18. Time: Screening, week 6, 12 and 18Description: Progression-free survival (PFS) starting from randomization to progression using RECIST 1.1 criteria.
Measure: To determine progression-free survival starting from randomization. Time: From randomisation until PD, median 10 months.Description: Rate and type of late adverse events
Measure: Long-term toxicities of intermittent dabrafenib + trametinib during treatment with pembrolizumab as compared to pembrolizumab monotherapy Time: From beyond week 18, up to 2 years follow-up.Description: As the short addition of dabrafenib+trametinib will induce for short time tumor regressions we will analyze cohorts 2-4 with a second baseline, namely the end of the targeted therapy at week 12, for progression free survival using to RECIST 1.1
Measure: To describe time to progression beginning from week 12 (cohorts 2-4). Time: Randomisation until week 12.Description: In addition to the primary readout (broadening of the melanoma-specific T cell response in peripheral blood), we will analyze the effect of the different therapy schemes on tumor immune cell infiltration (IHC for CD3, CD4, CD8, CD68, FoxP3, PD-L1, PD-L2, PD-1, CD11b, HLA).
Measure: Changes of immune parameters within the tumor. Time: 18 weeks from baseline.Allocation: Randomized
Parallel Assignment
There is one SNP
In addition to the primary readout (broadening of the melanoma-specific T cell response in peripheral blood), we will analyze the effect of the different therapy schemes on tumor immune cell infiltration (IHC for CD3, CD4, CD8, CD68, FoxP3, PD-L1, PD-L2, PD-1, CD11b, HLA).. Inclusion Criteria: - Adults at least 18 years of age - World Health Organization (WHO) Performance Status 0-2 - Histologically/cytologically confirmed stage IV BRAF V600E or K metastatic melanoma - Measurable disease according to RECIST 1.1 - At least one easy accessible lesion (s.c., lymph node) that can be repeatedly biopsied - Patient willing to undergo triple tumor biopsies during screening, at week 6, week 8 (cohorts 2-4 only), week 12, at week 18, and in case of disease progression. --- V600E ---
Inclusion Criteria: - Adults at least 18 years of age - World Health Organization (WHO) Performance Status 0-2 - Histologically/cytologically confirmed stage IV BRAF V600E or K metastatic melanoma - Measurable disease according to RECIST 1.1 - At least one easy accessible lesion (s.c., lymph node) that can be repeatedly biopsied - Patient willing to undergo triple tumor biopsies during screening, at week 6, week 8 (cohorts 2-4 only), week 12, at week 18, and in case of disease progression. --- V600E ---