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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

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

Name: Dabrafenib

Type: Drug

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

Name: Trametinib

Type: Drug

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

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

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:
Cutaneous melanoma
Genes 15
HRAS MITF CDKN2A BRAF NRAS NRAS WRN CDKN2A CXCR4 BAP1 POLH CDK4 ERCC3 XPC MC1R
Melanoma
Genes 98
MGMT NRAS POT1 NRAS XPA CTSC BRCA1 SDHC ERCC4 CXCR4 RAD51C CDKN2B ERCC3 XPC PALLD ERCC2 ERCC2 CHEK2 CDKN2A RAD51D GNAQ SDHD KRAS MBTPS2 BAP1 BAP1 CYSLTR2 RNF43 BAP1 CDKN2A PTPN11 CDK4 BRCA2 ERCC3 MITF TERF2IP ERCC4 CHEK2 BRCA1 TRPV3 POT1 OCA2 TERT CDKN2A AKT1 CDKN2A SF3B1 ERCC6 ERCC5 ERCC5 MDM2 BRCA2 BAP1 GNA11 ACD BRIP1 HRAS MRE11 BRAF TYR TP53 KLLN SEC23B PTEN PIK3CA XPA PERP MITF RAF1 BRAF POLH TP53 BARD1 NRAS SMAD4 RAD50 DDB2 ERCC2 NBN TERT MC1R SLC45A2 WRN PALB2 DDB2 PALB2 CDKN2A SDHB MC1R RAD51 TP53 XPC ERCC3 PTEN CDKN2A POLH CDK4 MC1R