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Report for Clinical Trial NCT01942993

Developed by Shray Alag, 2020.
SNP Clinical Trial Gene

The Effect of BRAF Inhibition With Vemurafenib On The Innate and Adaptive Immune Systems in Patients With Unresectable Stage III or Stage IV Melanoma Expressing a V600 BRAF Mutation

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.

NCT01942993 Melanoma
MeSH: Melanoma
HPO: Cutaneous melanoma Melanoma

1 Interventions

Name: Vemurafenib

Description: Vemurafenib will be administered at the FDA approved dose of 960 mg approximately 12 hours apart with or without a meal. Vemurafenib is provided at 240-mg film-coated tablets packed in bottles for oral administration. Vemurafenib should be swallowed whole with a glass of water and the medication should not be chewed or crushed. Management of symptomatic adverse events may require dose reductions, treatment interruptions, or treatment discontinuation. Dose reductions below 480 mg twice daily are not recommended.

Type: Drug

Vemurafenib


Primary Outcomes

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 after initiation of vemurafenib treatment as compared to baseline

Measure: Changes in the immune cellular signature in the blood circulation

Time: baseline and day 8

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 57 after initiation of vemurafenib treatment as compared to baseline

Measure: Changes in the immune cellular signature in the blood circulation

Time: baseline and day 57

Secondary Outcomes

Description: 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 after initiation of vemurafenib treatment as compared to baseline

Measure: Changes in the immune cellular signature in the tumor

Time: baseline and day 8-10

Description: 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 as compared to baseline.

Measure: Changes in Transcriptional Profile in the blood

Time: baseline and day 8

Description: 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 57 as compared to baseline.

Measure: Changes in Transcriptional Profile in the blood

Time: baseline and day 57

Description: 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 8-10

Description: change in dendritic cell function at day 8 as compared to baseline

Measure: Changes in Dendritic Cell function in Blood

Time: baseline and day 8

Description: change in dendritic cell function at day 57 as compared to baseline

Measure: Changes in Dendritic Cell function in Blood

Time: baseline and day 57

Description: 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 8-10

Description: Changes in macrophage function in blood at day 8 as compared to baseline

Measure: Changes in Macrophage Function in Blood

Time: baseline and day 8

Description: Changes in macrophage function in blood at day 57 as compared to baseline

Measure: Changes in Macrophage Function in Blood

Time: baseline and day 57

Description: 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 8-10

Description: changes in global T cell function in blood on day 8 as compared to baseline

Measure: Changes in Global T cell function in Blood

Time: baseline and day 8

Description: changes in global T cell function in blood on day 57 as compared to baseline

Measure: Changes in Global T cell function in Blood

Time: baseline and day 57

Description: 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 8-10

Description: Changes in Tumor Antigen Specific T cell Function using CD154 induction assay on day 8 as compared to baseline

Measure: Changes in Tumor Antigen Specific T cell Function in blood

Time: baseline and day 8

Description: Changes in Tumor Antigen Specific T cell Function using CD154 induction assay on day 15 as compared to baseline

Measure: Changes in Tumor Antigen Specific T cell Function in blood

Time: baseline and day 15

Description: Changes in Tumor Antigen Specific T cell Function using CD154 induction assay on day 126 as compared to baseline

Measure: Changes in Tumor Antigen Specific T cell Function in blood

Time: baseline and day 126

Description: 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 8-10

Description: changes in tumor burden using CT or MRI imaging studies

Measure: response to vemurafenib treatment

Time: up to 57 days

Description: development of cutaneous squamous cell carcinomas assessment

Measure: Development of Cutaneous Squamous Cell Carcinomas

Time: up to one year

Purpose: Treatment

Single Group Assignment


There is one SNP

SNPs


1 V600E

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 ---



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