The Effects of Treatment With Vemurafenib on the Immune System in Advanced Melanoma
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|ClinicalTrials.gov Identifier: NCT01942993|
Recruitment Status : Terminated (standard of care has changed)
First Posted : September 16, 2013
Results First Posted : September 30, 2020
Last Update Posted : September 30, 2020
|Condition or disease||Intervention/treatment||Phase|
|Melanoma||Drug: Vemurafenib||Phase 2|
Approximately 40-60 % of cutaneous melanomas select for a mutation in the BRAF protein which is part of a signaling pathway called the Mitogen Activated Protein Kinase (MAPK) pathway. Over 90% of mutations in BRAF occur at position V600 with the most common being a V600E mutation. Mutation at position V600 of BRAF activates the MAPK pathway which facilitates melanoma proliferation and growth. The response rate to treatment with vemurafenib in patients with stage IV melanoma expressing a V600E BRAF mutation is approximately 50%. A phase III study comparing first line treatment with vemurafenib compared to standard dacarbazine chemotherapy demonstrated a statistically significant overall survival benefit in this patient population. Based on this survival benefit vemurafenib was FDA approved for treatment of stage IV melanoma expressing a V600E BRAF mutation. Vemurafenib is administered at a dose of 960 milligrams orally twice daily.
While targeting BRAF can lead to survival benefits in patients with melanoma expressing BRAF mutation it is becoming increasingly apparent that the immune system is important in modulating the growth of melanoma. As such there are immune therapies FDA approved for the treatment of stage IV melanoma including ipilimumab which confers an overall survival benefit by activating the immune system through inhibition of the CTLA-4 protein expressed on certain T-cells. Little is known about how the exposure of different classes of immune cells to vemurafenib modulates the activity of the immune system. We do know that many melanomas express differentiation antigens which could potentially be recognized by the immune system. This recognition could potentially be utilized in the development of novel immunotherapeutic treatment approaches. The pharmacologic inhibition of the MAPK pathway does lead to increased expression of various melanoma differentiation antigens along with improved recognition by antigen-specific T-lymphocytes. Evaluation of a limited number of tumor biopsy specimens suggest that the infiltration of melanomas by CD4+ and CD8+ T-lymphocytes markedly increases following treatment with a BRAF inhibitor. Furthermore the viability and function (determined using assays for cytokine release assays and cytotoxic activity) of T-lymphocytes was not negatively affected by exposure to vemurafenib at concentrations known to cause anti-tumor effects.
The MAPK pathway is a pathway utilized by many cell types including immune cells and cells in the tumor microenvironment. As such vemurafenib could potentially modulate the activity of the MAPK pathway in the melanoma cells, immune cells, and components of the tumor microenvironment. Effects of vemurafenib on tumor cells may directly lead to changes in antigen presentation and effects on the innate and adaptive immune systems could potentially alter recognition of tumor cells and modulate positively or negatively immune recognition and antitumor activity. Therefore, a better understanding of immune modulation induced by anti-BRAF therapy should provide data to model and develop in a more rational fashion therapies which combine BRAF targeted and immune modulatory agents potentially using such agents as ipilimumab or anti-PD1 or anti-PDL1 antibodies.
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||3 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||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|
|Study Start Date :||September 2013|
|Actual Primary Completion Date :||November 2015|
|Actual Study Completion Date :||November 2015|
960 mg (four tablets of 240 mg each) of vemurafenib PO BID
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.
- Changes in the Immune Cellular Signature in the Blood Circulation [ Time Frame: baseline, day 8, and day 57 ]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
- Changes in the Immune Cellular Signature in the Tumor [ Time Frame: baseline, day 8-10, and day 57 ]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
- Changes in Transcriptional Profile in the Blood [ Time Frame: baseline, day 8, and day 57 ]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.
- Change in Transcriptional Profile in Tumor [ Time Frame: baseline and day 8-10 ]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.
- Changes in Dendritic Cell Function in Blood [ Time Frame: baseline day 8, and day 57 ]change in dendritic cell function at day 8 and day 57 as compared to baseline
- Changes in Dendritic Cell Function in Tumor [ Time Frame: baseline and day 8-10 ]Changes in dendritic cell function in tumor on day 8-10 as compared to baseline
- Changes in Macrophage Function in Blood [ Time Frame: baseline, day 8, and day 57 ]Changes in macrophage function in blood at day 8 and day 57 as compared to baseline
- Changes in Macrophage Function in Tumor [ Time Frame: baseline and day 8-10 ]changes in macrophage function in tumor on day 8-10 as compared to baseline
- Changes in Global T Cell Function in Blood [ Time Frame: baseline, day 8, and day 57 ]changes in global T cell function in blood on day 8 and day 57 as compared to baseline
- Changes in Global T Cell Function in Tumor [ Time Frame: baseline and day 8-10 ]Changes in Global T cell function in Tumor on day 8 as compared to baseline
- Changes in Tumor Antigen Specific T Cell Function in Blood [ Time Frame: baseline, day 8, day 15 and day 126 ]Changes in Tumor Antigen Specific T cell Function using CD154 induction assay on day 8, day 15 and day 126 as compared to baseline
- Changes in Histocytometry of Tumor [ Time Frame: baseline and day 8-10 ]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.
- Response to Vemurafenib Treatment [ Time Frame: up to 57 days ]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),
- Number of Participants Who Developed of Cutaneous Squamous Cell Carcinomas [ Time Frame: up to 5 months ]Number of participants who developed cutaneous squamous cell carcinomas while on the study
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01942993
|United States, New York|
|Icahn School of Medicine at Mount Sinai|
|New York, New York, United States, 11103|
|Principal Investigator:||Philip Friedlander, MD, PhD||Icahn School of Medicine at Mount Sinai|