Sorafenib for Patients With Extensive Keloids
Treatment of keloid disorder is an area of unmet medical need. Current treatments for keloid partially address small and localized keloids, yet there are no wholly satisfactory or effective treatments for patients with extensive keloids. Such patients may benefit from effective systemic treatments.
Sorafenib has the potential to regulate the three known dysregulated biological pathways in keloid tissue.
|Study Design:||Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||Phase II Trial of Sorafenib in Patients With Extensive Keloids|
- Response Rate (RR) of extensive keloids to sorafenib. RR is the sum of Complete Remission (CR) and Partial Remission (PR) at 12 month after last dose of sorafenib. [ Time Frame: 12 months ] [ Designated as safety issue: No ]The primary objective of this trial is to demonstrate the efficacy of sorafenib in patients with extensive keloids.
- The secondary endpoint of this trial is to demonstrate the rate of AE and SAE following exposure to sorafenib measured while on treatment as well as at 1 year after the last dose of sorafenib. [ Time Frame: 12 months ] [ Designated as safety issue: Yes ]The secondary objective of this trial is to demonstrate safety of sorafenib in this setting. Patients will be followed for one year after their last dose of sorafenib to assess safety of the treatment.
|Study Start Date:||March 2013|
|Estimated Study Completion Date:||September 2016|
|Estimated Primary Completion Date:||December 2015 (Final data collection date for primary outcome measure)|
Experimental: Sorafenib arm
All patients will be treated with sorafenib.
Treatment will be administered on an outpatient basis. All patients will keep a drug diary in order to record compliance with their drug regime. Sorafenib will be taken orally. Maximum length of treatment is 6 months. Starting dose of sorafenib is 200 mg three times per week for one month. In absence of Grade 2 toxicity, the dose will be increased on a monthly basis and will stop at 400 mg twice daily.
Other Name: Nexavar (sorafenib)
Dysregulation of several intracellular pathways have been reported by various investigators.
[A] Dysregulated apoptosis pathway: p53 mutations have been found in both hypertrophic scar and keloids fibroblasts from cultured cells to various extents. p53 plays a central role in the DNA damage response by inducing cell cycle arrest and/or apoptotic cell death. Time course experiments making cell cultures at different times to investigate the phenomenon of apoptosis and its involvement in the process of pathological scarring in both hypertrophic scars and keloid indicate to dysregulation of apoptotic pathways in Keloid tissue.
[B]Dysregulated TGF- β signaling: Transforming growth factor- β1 (TGF- β1) is well known as the crucial fibrogenic cytokine promoting ECM production and tissue fibrosis in keloid forming . TGF- β1 is an essential profibrotic cytokine for collagen synthesis, and it is well known to increase mRNA expression of procollagen I. Administration of TGF- β1 resulted in a dramatic increase in intracellular collagen I levels in keloid fibroblasts. Due to the close relationship between TGF- β signaling and the production of collagen, blocking TGF- β signaling has the potential of repressing fibroblast proliferation and collagen synthesis, thereby preventing the formation of keloids.
[C]Dysregulated VEGF signaling pathway: VEGF (Vascular endothelial growth factor), one of the most widely studied secreted factors involved in angiogenesis, has been implicated as crucial to normal and pathological wound healing . Gira et al.  indicated that VEGF production is abundant in the underlying dermis of keloids. In vitro studies have indicated that VEGF is expressed at higher levels in keloid-derived Fibroblasts than in normal skin Fibroblasts.
Sorafenib is an orally active multikinase inhibitor and has been reported to be an effective inhibitor of apoptosis, TGF-β signaling and VEGF pathway signaling, making it an ideal drug to test in the setting of extensive keloid disorder.
|United States, New York|
|Michael H. Tirgan, MD|
|New York, New York, United States, 10023|
|Principal Investigator:||Michael H Tirgan, MD||St. Luke's Roosevelt Hospital Center, New York City|