A Phase I/II Study to Determine the Feasibility and Efficacy of the Triple Combination of Oblimersen (OBL), Abraxane (ABX), and Temozolomide (TMZ) in Metastatic Melanoma and Normal LDH

9027 Background: OBL plus dacarbazine was significantly more efficacious than dacarbazine alone in patients with advanced melanoma (Bedikian et al, JCO, 2006). The OBL-dacarbazine regimen provided maximum benefit in patients with normal baseline LDH based on all endpoints, including survival (median, 11.4 vs. 9.7 months [p=0.018]). TMZ is an orally administered chemotherapy with a mechanism of action and efficacy in melanoma similar to that of dacarbazine (Middleton et al, JCO, 2000). ABX (albumin-bound paclitaxel) is currently being explored in melanoma (Hersh et al, JCO, 2005) An OBL-TMZ-ABX combination was synergistic preclinically, and a Phase I/II study of this combination initiated. Methods: Eligible are chemotherapy-naive patients with advanced melanoma, baseline LDH ≤1.1 x ULN, and measurable disease (RECIST). Treatment includes OBL 7 mg/kg/d (continuous IV infusion, days 1–7 and 22–29), TMZ 75 mg/m2/d (days 1–42), and ABX 175 mg/m2 (days 7 and 29) in Cohort 1 and 260 mg/m2 in Cohort 2 for four 56-day cycles. Serial serum samples are obtained for OBL and ABX pharmacokinetics. Pre- and post-tumor biopsies and PBMCs are monitored for Bcl-2 and proliferation markers and correlated with clinical response. Results: All 14 (1-M1a, 5-M1b, 8-M1c) patients planned for Cohort 1 have been enrolled; treatment is ongoing in 10. Grade 3–4 adverse events have been limited to 1 pt with neutropenia and 1 pt with thrombocytopenia. Four patients have achieved a partial response (>50% tumor reduction) lasting > 2 cycles (range: 3–6 cycles); 2 stable disease lasting 3 cycles; and 2 PD after 1 cycle. In 6, it is too early to assess response. IHC markers show a significant reduction in Bcl-2, a proportional increase in Bak and BCLxl, and no change in caspase activity. OBL and TMZ have no effect on ABX pharmacokinetics. Shed cryptic epitopes measured serially correlate with clinical responses. Conclusions: Tumor and serologic assessment of biomarkers correlate with clinical and radiologic responses or progression. Prolonged clinical activity has been seen and the regimen is safe and well tolerated. Cohort 2 is open to enrollment. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Genta Genta Abraxis, Genta