Pharmacokinetics Of Albumin-Bound Paclitaxel (Abx) In Combination With Temozolomide (Tmz) And Oblimersen Sodium (Obl) In Patients With Advanced Melanoma

20030 Background: ABX is a novel formulation of paclitaxel which has improved tolerability and can be given at higher doses than paclitaxel. Preclinical data has demonstrated synergy when ABX was added to OBL and TMZ in an A375 melanoma cell line. This Phase I/II study was performed to evaluate the safety, efficacy, and pharmacokinetics of ABX combined with TMZ and OBL in advanced melanoma. Methods: To date, 14 chemotherapy-naïve patients with unresectable stage III or stage IV melanoma and a normal LDH have been enrolled. The treatment consists of TMZ 75mg/m2 orally on days (d) 1–42, OBL 7mg/kg/d by continuous IV infusion on d 1–7 & 22–28, and ABX as a 30 minute IV infusion at 175 mg/m2 (Cohort 1) on d 8 & 29, every 8 weeks. Samples for determination of plasma paclitaxel concentration were taken on day 8 at 0, 0.5, 1, 2, 3, 4, and 6 hours (hr) after the start of the ABX infusion, and on day 9 at 24 hr after the start of the ABX infusion. The assay of paclitaxel employed solid-phase extraction of the drug from plasma and reverse-phase high-performance liquid chromatography. Pharmacokinetic parameter estimates of the decay data employed a two-compartment continuous-infusion model available in WinNonlin, Ver 5.2. Results: The results of the key pharmacokinetic estimates for paclitaxel for 10 patients who were evaluable are summarized in Table 1 along with a comparison of the 175 mg/m2 dose level from the Phase I trial of weekly ABI-007 (Nyman et al, JCO 23:7785–7793, 2005). The AUC estimates of paclitaxel exposure after 7 days of OBL and TMZ demonstrated reasonable agreement with the exposure of patients who received ABX alone. The lower elimination half-life estimates are due to the 24 hr PK sampling in our study compared to the additional sampling points evaluated in the 48 hr collections carried out in the Phase I study with ABX. Conclusions: In this first reported trial of ABX in combination with TMZ and OBL in advanced melanoma, no alterations in paclitaxel pharmacokinetics have been observed. Study Cmax, μg/ml AUC (μg *hr/ml) t ½(hr) ATG (n=10) 6.11 ± 2.73 9.37 ± 4.17 7.89 ± 3.25 Phase I ABI-007 (weekly 175 mg/m2), n=3 9.8 ± 6.2 6.87 ± 2.05 18.5 ± 1.73 Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Genta Abraxis Oncology, Genta