Background: Sorafenib has a low single agent RR in sarcoma. Other angiogenesis inhibitors are more effective when combined with standard chemotherapy. Sorafenib has been safely combined with dacarbazine for treatment of melanoma. As PRs, MRs and prolonged SD were seen in LMS, SS and MPNST in our single agent S study, we chose to investigate S+D in those histologies. Methods: Patients with LMS, SS or MPNST with up to 2 priors, and adequate hepatic, renal and marrow function receive S at 400 mg BID and D at 1000mg/m² every 3 weeks. Pts are restaged every 2 cycles. The primary objective of this trial is to determine Clinical Benefit Response rate (CBR=CR+PR + SD x18 weeks) of S+D in these subtypes. A Simon two stage design to distinguish between a CBR rate of 20% and 40% required 4 CBRs out of the first 17 pts to expand to a second cohort, and 11/37 (29.7%) CBRs to be considered positive. Results: From 2/09-12/10, 31 pts have been enrolled: 17 F, 14 M; median age 55, range 27-80; ECOG PS 0 16, 1 14; 20 Previously treated, avg 1.6 prior lines of therapy; Histology - LMS 17, SS 10, MPNST 4. 157 cycles of therapy have been administered. Thus far the CBR is 29% (9/31 – 6 LMS, 3 SS, 0 MPNST). The TTP is 11 weeks. The 3 and 6 month PFR rates are 35% and 26%. The Choi RR (10% decrease in unidimensional disease) is 19% (6/31), whereas the RECIST RR was 10% (3/31). OS is 13.2 months. 15 of the first 25 pts required D dose reductions for hematologic toxicity (platelets and neutrophils). One pt had fatal neutropenic fever, possibly related to treatment. Non- hematological toxicity is similar to what has been reported for S and D. A protocol amendment reduced the dose of D to 850 mg/m², and none of the subsequent 7 pts have required dose reduction. Conclusions: S+D can stabilize disease in up to 29% of pts with these subtypes, especially SS and LMS. Hematologic toxicity seems greater than D alone but is well tolerated with reduced D dose. CBR appears to be promising.