Phase I trial of dacarbazine and bortezomib in melanoma and soft tissue sarcoma
18008 Background: Dacarbazine (D) has modest single agent activity against melanoma and soft tissue sarcomas. NFκB is a transcription factor that in general promotes cell survival and antagonizes apoptosis. In melanoma NFκB is constitutively activated and increases further in response to D. Bortezomib (B) is a prosteasome inhibitor that down-regulates NFκB. In tissue culture and xenograft melanoma models B potentiates anticancer effects of D and the related agent temozolomide. Methods: The primary objective is to identify recommended phase II doses for D+B administered weekly. Patients with advanced melanoma or sarcoma are enrolled in a traditional ‘3+3‘ dose escalation format. Results: Recommended phase II doses will be at least D 250 mg/m2 and B 1.6 mg/m2, and dose escalation continues. Treatment has been generally well tolerated with known D and B toxicities. Among 8 melanoma patients there is 1 partial response (PR), 1 with stable disease on treatment 15 weeks, 6 with progressive disease (PD) 6, 7, 8, 8, 13, and 13 weeks. Among 5 sarcoma patients there is 1 PR and 4 with PD 4, 8, 16, and 24 wks. Conclusions: At full dose B and moderate dose D for this schedule, D+B is feasible and generally well-tolerated. Activity beyond that of D alone is not apparent to date, but several or all patients have been treated at less than maximum tolerated doses. [Table: see text]