A Randomized Discontinuation, Blinded, Placebo-Controlled Phase II Study of Sorafenib in Patients With Chemonaive Metastatic Uveal Melanoma

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 (Scheulen et al, 2011). These treatment results are encouraging for further investigation of treatment with sorafenib in patients with metastatic uveal melanoma in a randomized trial, a potential benefit of this systemic treatment is anticipated.

Rationale for selection of a randomized discontinuation trial design The randomized discontinuation trial (RDT) design , first proposed in 1975 (Amery et al, 1975) aims to assess the clinical activity of a drug while minimizing the use of placebo. All patients receive study drug for an initial run-in period, followed by random assignment of potential responders to either the study drug or the placebo (Amery et al,1975; Kopec et al,1993). RDT design provides more homogeneous study treatment groups by selecting patients with a predefined response, and allows the evaluation of a drug's clinical activity with fewer patients and increased statistical power. Thus this study design is especially useful to distinguish anticancer activity of the drug and natural history of the underlying disease (Kopec et al,1993; Jain L et al, 2006; Rosner et al, 2002). As pointed out by Rosner the RDT design is a feasible phase II study design for evaluating possible activity of cytostatic anticancer agents whereas historically anticancer drug efficacy was evaluated as being cytotoxic (Rosner et al, 2002).

As laid down in section 3.2 sorafenib is an oral multi-kinase inhibitor that targets the Raf/MEK/ERK signaling pathway in the cell and receptor tyrosine kinases (RTKs) such as VEGFR-2, VEGFR-3, and PDGFR-ß involved in tumor cell proliferation and angiogenesis. The primary clinical benefit of sorafenib is expected to be disease stabilization rather than tumor shrinkage. As disease stabilization is substantially influenced by the natural disease of a disease, the RDT design was chosen in several phase II trials evaluating possible activity of sorafenib (such as Ratain et al, 2006; Eisen et al, 2006; Pacey et al, 2009) Taking into account that uveal melanoma is a rare disease with presumably unidentified prognostic factors the RDT design seems to be useful for objective evaluation of time to progression and overall survival.