Oblimersen 1-hour IV infusion in combination with temozolomide and albumin-bound paclitaxel in patients with advanced melanoma.

Abstract

8561 Background: Oblimersen (OBL), temozolomide (TMZ), and albumin-bound paclitaxel (ABP) are synergistic in melanoma cell lines. We recently reported promising results with this regimen in 18 patients with advanced melanoma and normal LDH. OBL was given as a 7-day continuous IV infusion (7 mg/kg/d, day 1-7, 22-28) in combination with TMZ (75 mg/m2/d, day 1-42) and ABP (175 or 260 mg/m2, day 7, 28 after OBL) in 56-day cycles. Response rate (33%) included 1 CR lasting > 25 months and 5 PRs lasting > 2 cycles. Seven pts (39%) had SD > 3 cycles and 5 (28%), disease progression. Based on the safety profile and PK of OBL given by short IV infusion, we evaluated a fixed dose of OBL given as a 1-hour IV infusion with TMZ and ABP. Methods: Chemotherapy-naïve patients with advanced melanoma, ECOG PS ≤ 2, and baseline LDH ≤ 1.1 × ULN received TMZ 75 mg/m2/d orally (day 1-42), OBL 900 mg as a 1-hour IV infusion (days 1,4,8,11,22,25,29,32), and ABP 175 mg/m2 as a 30-minute IV infusion (days 4,25) in 56-day cycles. Responses were evaluated per RECIST. Blood samples were obtained for OBL and ABP PK, and measurement of serum shed cryptic epitopes. Immunohistochemistry (IHC) staining for Bcl-2, Bcl-XL, BAK, and caspase 3 was performed on days -1, 4, and 28 tumor samples. Results: Ten patients have been treated with the OBL one-hour infusion. Two patients progressed after one cycle. Eight patients are continuing treatment; 3 have a PR, 4 have SD and one has not been evaluated yet. One patient with a PR demonstrated increased intra-tumoral caspase 3 and decreased Bcl-2 on day 4 due to an overall reduction in tumor burden, which correlated with a decrease in shed collagen epitopes and clinical response. The one-hour OBL IV infusion has been well tolerated. No grade 3 or 4 events other than a grade 3 preexisting pleural effusion have occurred. Planned enrollment of 14 pts is continuing. Conclusions: Preliminary data from this ongoing study appear to confirm the promising response and disease-control rates observed with this drug combination using a substantially more convenient dosing regimen. The OBL 1-hour IV infusion is well tolerated in combination with TMZ and ABP. Additional clinical data, as well as PK and IHC data, will be presented. No significant financial relationships to disclose.