Clinical Trial: A Study of Sorafenib in Patients With Chemonaive Metastatic Uveal Melanoma
Study Status: Active, not recruiting
Recruit Status: Active, not recruiting
Study Type: Interventional
Official Title: A Randomized Discontinuation, Blinded, Placebo-Controlled Phase II Study of Sorafenib in Patients With Chemonaive Metastatic Uveal Melanoma
Brief Summary:
Uveal melanoma is the most common primary intra-ocular malignancy in adults with an incidence of 0.6 - 0.7 per 100,000 per year.
Prognosis of metastatic uveal melanoma is poor. In retrospective analyses a median survival time after detection of metastases of 5 months (Flaherty et al, 1998) and 7 months (Kath et al, 1993) was reported. For patients receiving no treatment reported median survival was 2.0 months compared with 5.2 months for those receiving treatment for metastases (Gragoudas et al, 1991).
Up to now there is no established treatment of metastatic uveal melanoma. Some therapeutic approaches with locoregional treatment or systemic chemotherapy have been undertaken:
In case of metastatic disease which is confined to the liver in about 85% of patients with uveal melanoma surgical resection led to a median survival of 14 months (Mariani et al, 2009) or 19 months and a 5-year survival rate of 22% in a selected patient population (Adam et al, 2006).
As locoregional treatment option treatment with fotemustine via direct intra-arterial hepatic infusion was investigated and led to a median survival of 15 months (Peters et al, 2006). This was not a randomized trial, but a report on 101 consecutive treated patients. Additional debulking surgery was performed whenever feasible.
A randomized phase III trial comparing intra-arterial hepatic fotemustine administration with intravenous systemic fotemustine and overall survival as primary endpoint is still ongoing (EORTC 18021).
Thus, no systemic chemotherapy is approved for metastatic uveal melanoma. Although no specific genes have been linked to the pathogenesis of uveal melanoma
Detailed Summary:
Rationale for treatment of uveal melanoma with sorafenib Improved understanding of the molecular pathogenesis of cancers has led to a new generation of therapeutic agents that interfere with a specific pathway critical in tumor development or progression. Although no specific genes have been linked to the pathogenesis of uveal melanoma, which significantly differs from that of cutaneous melanoma, progress has been made in identifying potential targets involved in uveal melanoma apoptosis, proliferation, invasion, metastasis, and angiogenesis. Accordingly, improvement of systemic therapy of metastatic uveal melanoma could be achieved by using molecularly targeted agents that are currently in clinical use as well as agents being tested in clinical trials. Preclinical studies suggest potential benefit of inhibitors of Bcl-2, ubiquitin-proteasome, histone deactylase, mitogen-activated protein kinase and phosphatidylinositol-3-kinase-AKT pathways, and receptor tyrosine kinases. Modifiers of adhesion molecules, matrix metalloproteinase, and angiogenic factors also have demonstrated potential benefit. (Triozzi et al, 2008).
Thus, sorafenib as oral multi-kinase inhibitor that targets the Raf/MEK/ERK signaling pathway (CRAF, BRAF, V600E BRAF) in the cell and receptor tyrosine kinases (RTKs) such as VEGFR-2, VEGFR-3, and PDGFR-ß involved in tumor cell proliferation and angiogenesis may potentially lead to a benefit for patients with metastatic uveal melanoma in terms of disease control and prolongation of survival.
In a GCP-adapted register trial approved by the ethics committee in Essen 62 patients with metastatic uveal melanoma received treatment with sorafenib on a compassionate use basis. Median overall survival was 10.8 months in patients receiving 200 mg bid sorafenib and 7.1 months in patients receiving 400 mg bid (Scheu
Sponsor: Prof. Dr. med. Max. E. Scheulen
Current Primary Outcome: Progression Free Survival [ Time Frame: Every 8 weeks for 1 year ]
Original Primary Outcome: Prgression Free Survival [ Time Frame: Every 8 weeks for 1 year ]
Current Secondary Outcome:
- Number of patients with adverse events [ Time Frame: Every 8 weeks for 1 year ]
- Overall Survival [ Time Frame: Every 8 weeks for 2 years ]
Original Secondary Outcome: Same as current
Information By: University Hospital, Essen
Dates:
Date Received: June 14, 2011
Date Started: June 2011
Date Completion: June 2017
Last Updated: December 2, 2014
Last Verified: December 2014
