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Report for Clinical Trial NCT02625337

Developed by Shray Alag, 2020.
SNP Clinical Trial Gene

Phase 2 Study Comparing Pembrolizumab With Intermittent/Short-term Dual MAPK Pathway Inhibition Plus Pembrolizumab in Patients Harboring the BRAFV600 Mutation

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.

NCT02625337 Metastatic Melanoma
MeSH:Melanoma
HPO:Cutaneous melanoma Melanoma

5 Interventions

Name: Pembrolizumab

Type: Drug
Group Labels: 4

Pembrolizumab mono Pembrolizumab with dabrafenib+trametinib intermediate Pembrolizumab with dabrafenib+trametinib long Pembrolizumab with dabrafenib+trametinib short

Name: Dabrafenib

Type: Drug
Group Labels: 3

Pembrolizumab with dabrafenib+trametinib intermediate Pembrolizumab with dabrafenib+trametinib long Pembrolizumab with dabrafenib+trametinib short

Name: Trametinib

Type: Drug
Group Labels: 3

Pembrolizumab with dabrafenib+trametinib intermediate Pembrolizumab with dabrafenib+trametinib long Pembrolizumab with dabrafenib+trametinib short

Name: Biopsy

Description: Biopsies will be taken during screening, before randomization, at week 8 (only arm 2-4) after 12 weeks, at week 18 and if PD.
Type: Procedure
Group Labels: 4

Pembrolizumab mono Pembrolizumab with dabrafenib+trametinib intermediate Pembrolizumab with dabrafenib+trametinib long Pembrolizumab with dabrafenib+trametinib short

Name: Blood taking

Description: Blood will be taken for PBMCs during screening (twice), before randomization, at weeks 12 at week 18 and if PD.
Type: Procedure
Group Labels: 4

Pembrolizumab mono Pembrolizumab with dabrafenib+trametinib intermediate Pembrolizumab with dabrafenib+trametinib long Pembrolizumab with dabrafenib+trametinib short


Primary Outcomes

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 baseline

Description: 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.

Secondary Outcomes

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 18

Description: 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.

Other Outcomes

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.

Purpose: Treatment

Allocation: Randomized

Parallel Assignment


There is one SNP

SNPs


1 V600E

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 ---



HPO Nodes


HPO: