8545 Background: The combination (combo) of oblimersen (OBL), a bcl-2 anti-sense agent, with dacarbazine showed promise in metastatic melanoma (MM) patients (pts) with normal (nl) LDH. OBL, temozolomide (TMZ), and abraxane (ABX) were synergistic in preclinical models of A375 MM cell lines. We conducted a phase I trial of this combo in MM pts with nl LDH and will present the final analysis of toxicity (tox) and clinical efficacy. Methods: Chemo-naïve MM pts (ECOG PS≤2, nl LDH, measurable disease per RECIST) were enrolled onto a phase I protocol with 3 cohorts (ct). Treatment regimen consisted of 56-day cycles of OBL 7 mg/kg/d continuous IV infusion (CIV), d 1-7 and 22-28 in ct 1-2; OBL 900 mg fixed dose over 1 hour, twice weekly in weeks 1-2, 4-5 [d 1,4,8,11,22,25,29,32] for ct 3; TMZ 75/m2/d in ct 1-3, d 1-42, and ABX 175 mg/m2 in ct 1 and 3, 260 mg/m2 in ct 2, d 7 and 28. IHC staining for Bcl-2, Bcl-XL, BAK and caspase 3 were performed in pre- and post-therapy tumor samples. ABX and OBL PK and shed serum cryptic epitopes (SSCE) were monitored. Results: 32 pts were treated (ct 1-14; ct 2- 4; ct 3-14). Median age= 58 years (range: 34-78). Stage M1a-4; M1b-2; M1c-26. Average cycles=3. Tox, all ct: Gr III leukopenia (1), neutropenia (neut) (2), thrombocytopenia (thrombo) (1), sensory neuropathy (sens neuro) (2), OBL hypersensitivity (2); Gr IV neut (1), thrombo (1), sens neuro (4). Responses, all ct: 2-CR (48+ and 14 mos), 10-PR, 13-SD, 7-PD for a disease control rate (CR+PR+SD) of 78.1%. Survival, all ct: OS 14.7 mos; 50% survived > 1y. Correlates: No impact of combo on ABX PK. SSCE appeared to correlate with clinical response or disease progression. Alteration of the tumor biology based on phenotypic changes in Bcl-2, Bcl-xL, BAK and caspase 3 correlated with response to treatment. Conclusions: The combo of OBL, TMZ, and ABX in MM pts with nl LDH is safe and well tolerated. The disease control rate of 78.1% and the survival data are encouraging. Biomarker studies support the rationale that Bcl-2 antisense therapy specifically impacts apoptotic signaling pathways in MM cells. The twice-weekly, fixed-dose OBL schedule appears to be similar in safety and efficacy as the 7-day CIV regimen.