Survival of advanced melanoma patients with normal LDH treated with oblimersen, temozolomide, and nab-paclitaxel

Abstract

9080 Background: Oblimersen (OBL), temozolomide (TMZ), and abraxane (ABX) act synergistically in preclinical studies with melanoma cell lines. Bcl-2 antisense therapy in combination with dacarbazine was encouraging in advanced melanoma patients(pts) with normal LDH. Methods: Chemotherapy-naïve advanced melanoma pts (ECOG PS ≤ 2, baseline LDH ≤1.1 × ULN, measurable disease per RECIST) were enrolled on a phase I/II protocol. The treatment regimen consisted of 56-day cycles of OBL (7 mg/kg/d continuous IV infusion, d 1–7 and 22–28), TMZ (75 mg/m2/d, d 1–42), and ABX (175 mg/m2 in Cohort 1, 260 mg/m2 in Cohort 2, d 7 and 28). Immunohistochemical (IHC) staining for Bcl-2, Bcl-XL, BAK and caspase 3 was performed in pre- and post-therapy tumor samples. Serum shed collagen cryptic epitope levels were monitored. Results: 18 pts were treated (Cohort 1 = 14 pts [1–6 cycles];Cohort 2 = 4 pts [2–3 cycles]). Median age was 58 years (range: 34–78). Disease sites included liver (6), other visceral sites (10), skin, subcutaneous tissue, and lymph nodes (2). The overall survival (OS) was 14.7 months and showed a trend towards superiority when compared to both arms of the prior oblimersen trial (DTIC, OS 9.7 months, p = 0.078 and DTIC-OBL, OS 11.4 months, p = 0.31) in pts with the same LDH cut-off (Bedikian et al. JCO. 2006). 50% of pts survived > 1 year. One CR lasted 25+ mo, five PR (>50% tumor reduction) lasted > 2 cycles, and 7 SD lasted > 3 cycles. Five PD after 1 cycle were seen. One ocular melanoma pt survived 15 mo despite PD. Shed cryptic epitopes correlated with clinical response versus 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: Our data suggest that the combination of OBL, TMZ, and ABX is synergistic in advanced melanoma pts with normal LDH, possibly translating into improved OS compared to prior regimens with dacarbazine ± OBL. Biomarker studies support the rationale that Bcl-2 antisense therapy specifically impacts apoptotic signaling pathways in melanoma cells from metastatic tumor. The survival data in the limited number of pts enrolled in cohort 1 and 2 of this trial are encouraging; further exploration with this combination is underway using 1-hour infusions of OBL. No significant financial relationships to disclose.