This is an open-label, multi-center, clinical phase II study to explore the correlation of the genetic make-up of the treated tumor before start of therapy and to correlate clinical response at 8 weeks as well as metabolic response at 2 and 8 weeks with genetic features of the tumor. It will be conducted as a rationale optimization of targeted therapy in BRAF naïve and pretreated patients. Prerequisite for all patients is the availability of tumor sample at start of treatment in order to determine the underlying driver mutation (BRAF mutational status) as well as molecular composition by next generation sequencing (NGS) and assessable lesions for biopsy at week 2. Melanoma patients in stage III (non-resectable) and stage IV are sorted into Cohort A or B according to their previous BRAF-treatment and treated with dabrafenib and trametinib (cohort A and B)
Name: Dabrafenib
Description: 150 mg twice dailyType: DrugCohort A (BRAFi naïve) Cohort B (BRAFi / MEKi rechallenge)
Name: Trametinib
Description: 2 mg dailyType: DrugCohort A (BRAFi naïve) Cohort B (BRAFi / MEKi rechallenge)
Description: To broaden the understanding of molecular characterization of the melanoma in correlation to the clinical response (defined as partial or complete response according to RECIST) at week 8 of targeted therapy in different pre-treated patients with advanced/metastatic BRAF V600E/K mutation-positive cutaneous melanoma.
Measure: Correlation of clinical response at week 8 of targeted therapy with molecular results of the biopsies. Time: Week 8Description: To correlate the tumor´s molecular composition to metabolic responses and biological effects on the downstream signaling cascade in order to get first insights into an adaptive mechanism in the downstream signaling of an oncogenic driver mutation upon its selective inhibition.
Measure: Correlation of the tumor´s molecular composition to metabolic responses Time: Baseline, week 2 and 8Description: Occurrence of adverse events and reactions
Measure: Safety / toxicity according to the Common Toxicity Criteria (CTC, Version 4.0) Time: 1 yearDescription: Proportion of patients with PFS after date of the first dose of study medication until the first documented tumor progression date or date of death, whichever occurs first.
Measure: Progression free survival rate Time: 6 and 12 monthsDescription: Time after date of the first dose of study medication until documented date of death
Measure: Overall survival Time: 6 and 12 monthsDescription: Time after date of the first dose of study medication until the first documented tumor progression date or date of death, whichever occurs
Measure: Progression free survival according to RECIST criteria Time: 6 and 12 monthsDescription: Proportion of patients with PR and CR
Measure: Overall response rate according to RECIST criteria Time: 6 and 12 monthsDescription: Proportion of patients with SD, PR and CR
Measure: Disease control rate according to RECIST criteria Time: 6 and 12 monthsAllocation: Non-Randomized
Parallel Assignment
There is one SNP
Prerequisite for all patients is the availability of tumor sample at start of treatment in order to determine the underlying driver mutation (BRAF mutational status) as well as molecular composition by next generation sequencing (NGS) and assessable lesions for biopsy at week 2. Melanoma patients in stage III (non-resectable) and stage IV are sorted into Cohort A or B according to their previous BRAF-treatment and treated with dabrafenib and trametinib (cohort A and B) Correlation of clinical response at week 8 of targeted therapy with molecular results of the biopsies.. To broaden the understanding of molecular characterization of the melanoma in correlation to the clinical response (defined as partial or complete response according to RECIST) at week 8 of targeted therapy in different pre-treated patients with advanced/metastatic BRAF V600E/K mutation-positive cutaneous melanoma.. Correlation of the tumor´s molecular composition to metabolic responses. --- V600E ---
3. Histologically confirmed cutaneous melanoma that is either Stage IIIc (unresectable) or Stage IV (metastatic), and determined to be BRAF V600E/K mutation-positive by the central laboratory. --- V600E ---