SNS-595 demonstrates clinical activity and dose-proportional pharmacokinetics (PK) in two phase I clinical studies

Abstract

3062 Background: SNS-595 is a novel naphthyridine analog with broad and potent activity in preclinical models. Methods: SNS-595 was administered to patients (pts) with advanced solid cancers as an IV infusion over 10 minutes on 2 schedules: (A) qwk x3/1 week off, and (B) q3wks. Pt eligibility included refractory solid tumors and adequate organ function. Results: In study A, 20 patients (pts) were treated in 6 cohorts (dose range 3–24 mg/m2/wk). In study B, 41 pts were treated in 9 cohorts (dose range 3–75 mg/m2/wk). After the MTD in heavily pretreated (HP) pts was found, dose escalation in minimally pretreated (MP) pts was evaluated. The median ages were 60.5 yrs (A) and 59.5 yrs (B), sex 12F/8M (A), 16F/25M (B). All pts had a ECOG PS 0–2. Neutropenia was the dose limiting toxicity (DLT) for both studies. The MTD for A was 15 mg/m2 for HP and MP pts; the MTD for B was 48 mg/m2 for HP and 60 mg/m2 for MP pts. For both studies 2 pts had grade 4 thrombocytopenia; non-hematological toxicities were all grade 1/2. In A, pharmacokinetics (PK) were assessed on Days 1 and 15 (after the 1st and 3rd doses); exposure increased linearly over an 8-fold dose range (1.6–15 mcghr/mL), CL, Vss and T1/2 averaged 2 L/hr/m2, 49 L/m2, 18 hr, respectively, and did not change from Day 1 to 15. In B, PK were assessed on Day 1 after the 1st dose; exposure increased linearly over the 24-fold dose range (1.1–46 mcghr/mL), CL, Vss, and T1/2 averaged 2 L/hr/m2, 53 L/m2, and 21 hrs, respectively. For A, best responses were 4 SD (range 13–22 wks); for B, best responses were 1 PR and 12 SD (range 14–56 wks). Conclusion: SNS-595 was well tolerated and showed clinical activity with both qwk and q3wk dosing. The DLT was non-cumulative neutropenia. SNS-595 demonstrated remarkably predictable PK, with low inter-and intra-patient variability. Based on these data, phase 2 studies of SNS-595 as monotherapy are ongoing, and are planned in combination therapy. [Table: see text]