A Study to Evaluate RAF265, an Oral Drug Administered to Subjects With Locally Advanced or Metastatic Melanoma

The Ras/Raf/MEK/ERK pathway plays a prominent role in controlling several key cellular functions including growth, proliferation and survival. B-Raf is a member of the Ras/Raf/MEK/ERK pathway and is frequently mutated in melanoma resulting in activation of the MAPK pathway. RAF265 is a novel, orally active, small molecule with potent inhibitory activity against B-Raf kinase and additional antiangiogenic activity through inhibition of vascular endothelial growth factor receptor type 2 (VEGFR-2) in non-clinical studies.

The primary objectives of this study are to determine the maximum tolerated dose (MTD), dose limiting toxicities (DLTs), and the safety profile of RAF265 when administered orally to subjects with locally advanced or metastatic melanoma; to determine the plasma pharmacokinetics (PKs) of orally administered RAF265; and to evaluate potential pharmacodynamic effects of RAF265 using tumor biopsies, peripheral blood samples, and tumor imaging.

Inclusion criteria

• Confirmed diagnosis of melanoma, locally advanced AJCC Stage IIIB to metastatic Stage IV
• Measurable disease - at least one lesion measured in at least one dimension as ≥ 20 mm with conventional techniques or ≥ 10 mm with spiral computed tomography (CT) scan
• ECOG performance status of 0 or 1
• No concurrent anticancer or investigational therapy for at least 4 weeks prior to enrollment
• No major surgery for at least 4 weeks prior to enrollment

Exclusion criteria

• Significant cardiac disease or other significant medical/psychiatric disease
• History of primary central nervous system tumor or brain metastases
• History of melena, hematemesis, or hemoptysis within the last 3 months
• Previous therapy with certain molecularly targeted agents