Phase Ii Trial Of Sorafenib Combined With Dacarbazine In Metastatic Melanoma Patients.

8012 Background: Sorafenib inhibits tumor cell proliferation and angiogenesis through blockade of multiple kinases including Raf, VEGFR-2/-3, and PDGFR-β. In Phase I/II trials, sorafenib was generally well tolerated as a monotherapy or in combination with other agents. A Phase I study in combination with dacarbazine (DTIC) showed encouraging activity, which warranted this Phase II study. Methods: This multi-center, open-label, two-stage (30 patients in Stage 1; 52 in Stage 2), uncontrolled Phase II trial was performed to evaluate the primary endpoints of efficacy (according to RECIST) and tolerability of sorafenib in combination with DTIC in patients with advanced metastatic melanoma. Eligibility criteria included ECOG 0 or 1, life expectancy ≥12 weeks, adequate bone marrow, liver, and renal function. Oral sorafenib 400 mg twice daily (bid) was administered with repeated 3-week cycles of DTIC 1000 mg/m2. Results: At this interim end of Stage 1 analysis, 30 patients with metastatic melanoma had been treated (median age 61 years [range 30–78]; 73.3% male; 96.7% white). Five (16.7%) patients had PR as best response (two confirmed, three currently unconfirmed), 13 (43.3%) had SD, 10 (33.3%) had PD, and two (6.7%) were unevaluable for tumor response. The patients with confirmed PR continue on study drug at 6.4 months. Median progression-free survival for all patients was 3.6 months (range 0.9–6.1 months). The most frequently reported drug-related adverse events (AEs) were dermatologic (rash/desquamation [43%], hand-foot skin reaction [HFS, 33%]); gastrointestinal (constipation [47%], nausea [37%], diarrhea [27%]); constitutional (fatigue [43%]); and blood/bone marrow (neutrophils [40%], platelets [30%]). The most common grade 3/4 drug-related AEs were blood/bone marrow (neutrophils [23%], platelets [17%]), and fatigue (7%), while HFS and hypertension were observed in <5%. Conclusions: Continuous sorafenib 400 mg bid is generally well tolerated and shows promising preliminary anti-tumor activity in combination with DTIC. No toxicities were observed above those expected from either agent alone. Updated results will be presented, including the decision whether to proceed to Stage 2 of the study. [Table: see text]