Approximately 40-60 % of cutaneous melanomas select for a mutation in a protein called BRAF which is part of a signaling pathway called the Mitogen Activated Protein Kinase (MAPK) pathway. When BRAF is mutated the MAPK pathway remains active allowing for melanoma to grow. Vemurafenib is an oral treatment which blocks the activity of BRAF which leads to decreasing the activity of the MAPK pathway. When patients with melanoma expressing specific mutation in BRAF are treated with vemurafenib approximately 50% will develop a response to treatment with shrinkage of tumor. When compared to a standard chemotherapy called dacarbazine used to treat melanoma, treatment with vemurafenib leads to a statistically significant overall survival or living longer benefit. Because of this survival benefit vemurafenib was Food and Drug Administration (FDA) approved for the treatment of metastatic melanoma expressing a BRAF mutation called V600E BRAF. There is increasing evidence that the immune system can also be important in affecting melanoma growth and survival and there are immune treatments FDA approved for the treatment of metastatic melanoma. There is some limited evidence that blocking BRAF with vemurafenib may affect the activity of components of the immune system. It is important to better characterize and understand the effects of vemurafenib treatment on various components of the immune system. The purpose of this study is to systematically evaluate the effects of vemurafenib treatment (at FDA approved dosing regimen) on parts of the immune systems called the innate and adaptive immune systems. The hypothesis is that vemurafenib treatment will affect the immune system.
Name: Vemurafenib
Description: Immuno-fluorescence and flow cytometry will be performed on blood specimens obtained to determine changes in the immune cell signature in the blood on day 8 and day 57 after initiation of vemurafenib treatment as compared to baseline
Measure: Changes in the Immune Cellular Signature in the Blood Circulation Time: baseline, day 8, and day 57Description: Immuno-fluorescence and flow cytometry will be performed on tumor specimens obtained to determine changes in the immune cell signature in the tumor on day 8-10 and day 57 after initiation of vemurafenib treatment as compared to baseline
Measure: Changes in the Immune Cellular Signature in the Tumor Time: baseline, day 8-10, and day 57Description: Global changes in the blood transcriptome in response to vemurafenib therapy will be performed using gene expression arrays. Change in the blood transcriptosome on day 8 and day 57 as compared to baseline.
Measure: Changes in Transcriptional Profile in the Blood Time: baseline, day 8, and day 57Description: Global changes in the transcriptosome of tumor associated immune cells in response to therapy will be performed using gene expression arrays. The transcriptosome in tumor will be compared on purified tumor immune cells obtained from a pretreatment tumor biopsy performed at baseline and a second biopsy obtained after starting treatment and obtained between days 8-10.
Measure: Change in Transcriptional Profile in Tumor Time: baseline and day 8-10Description: change in dendritic cell function at day 8 and day 57 as compared to baseline
Measure: Changes in Dendritic Cell Function in Blood Time: baseline day 8, and day 57Description: Changes in dendritic cell function in tumor on day 8-10 as compared to baseline
Measure: Changes in Dendritic Cell Function in Tumor Time: baseline and day 8-10Description: Changes in macrophage function in blood at day 8 and day 57 as compared to baseline
Measure: Changes in Macrophage Function in Blood Time: baseline, day 8, and day 57Description: changes in macrophage function in tumor on day 8-10 as compared to baseline
Measure: Changes in Macrophage Function in Tumor Time: baseline and day 8-10Description: changes in global T cell function in blood on day 8 and day 57 as compared to baseline
Measure: Changes in Global T Cell Function in Blood Time: baseline, day 8, and day 57Description: Changes in Global T cell function in Tumor on day 8 as compared to baseline
Measure: Changes in Global T Cell Function in Tumor Time: baseline and day 8-10Description: Changes in Tumor Antigen Specific T cell Function using CD154 induction assay on day 8, day 15 and day 126 as compared to baseline
Measure: Changes in Tumor Antigen Specific T Cell Function in Blood Time: baseline, day 8, day 15 and day 126Description: Changes in Histocytometry of tumor on day 8-10 as compared to baseline. Histocytometry is a novel microscopic analytical method (Gerner et al. 2012) which combines the advantages of flow cytometry and Microscopic techniques. This techniques allows for the visualization and quantification of phenotypically complex cellular subsets and provides spatial and cell-cell interactions.
Measure: Changes in Histocytometry of Tumor Time: baseline and day 8-10Description: Response to vemurafenib treatment based on changes in tumor burden using CT or MRI imaging studies. Response are categorized as complete response (CR), partial response (PR), progressive disease (PD), and stable disease (SD),
Measure: Response to Vemurafenib Treatment Time: up to 57 daysDescription: Number of participants who developed cutaneous squamous cell carcinomas while on the study
Measure: Number of Participants Who Developed of Cutaneous Squamous Cell Carcinomas Time: up to 5 monthsAllocation: N/A
Single Group Assignment
There is one SNP
Because of this survival benefit vemurafenib was Food and Drug Administration (FDA) approved for the treatment of metastatic melanoma expressing a BRAF mutation called V600E BRAF. --- V600E ---
Over 90% of mutations in BRAF occur at position V600 with the most common being a V600E mutation. --- V600E ---
The response rate to treatment with vemurafenib in patients with stage IV melanoma expressing a V600E BRAF mutation is approximately 50%. --- V600E ---
Based on this survival benefit vemurafenib was FDA approved for treatment of stage IV melanoma expressing a V600E BRAF mutation. --- V600E ---