SNS-595, a Novel S-Phase Active Cytotoxic, Demonstrates Pharmacologic Properties Appropriate for the Treatment of Advanced Hematologic Malignancies.

Despite advances in the treatment of leukemia patients, response rates with intensive chemotherapy regimens remain less than 30% for relapsed or refractory acute leukemias and advanced chronic myelogenous leukemias. SNS-595, is a novel naphthyridine analog small molecule, a class of drugs not previously used in cancer treatment. SNS-595 acts specifically during the S-phase of the cell cycle to induce rapid apoptosis of cells that are actively synthesizing DNA, and a subsequent cell cycle arrest in the G2 phase of the cell cycle. Sunesis Pharmaceuticals, Inc., is developing SNS-595 for the treatment of both solid and hematologic malignancies. SNS-595 was previously evaluated in two models of hematologic cancer in nu/nu mice, causing a dose-dependent tumor growth inhibition (97% to 99%, n=6 mice per treatment group) in a LM-3 Jck (human acute lymphoma) hematologic xenograft. All 6 mice treated at 30 mg/kg had a major reduction in tumor volume, with 2 mice showing a complete response. SNS-595 also significantly inhibited tumor growth in mice bearing CCRF-CEM (human acute lymphoblastic leukemia) xenograft tumors. In phase I clinical trials in solid tumors the dose-limiting toxicity was neutropenia, and the incidence of gastrointestinal effects, nausea, and vomiting was low. No mucositis or peripheral neuropathies were observed. In the present study, CD1 mice (n=4 per treatment group) were administered either SNS-595 15 mg/kg or 20 mg/kg, by IV bolus on days 0 and 4, or the S-phase acting drug, cytarabine (Ara-C) 150 mg/kg, BID, by IP injection on days 0 and 4. SNS-595 was well tolerated, with no body weight loss observed through to day 16. Bone marrow isolated from the femurs showed a dose-dependent reduction in cellularity on day 6, 48hr after the second of the two SNS-595 administrations; at 15 and 20 mg/kg, cellularity was reduced to 15% (±2.9, n=4) and 7.5% (±1.4, n=4) respectively. SNS-595, 20 mg/kg, reduced absolute neutrophils to a nadir of 51 ±24 cells/μL blood (n=4) on day 8, from 1244 ±55 cells/μL at day 0 (n=4), but subsequently rebounded to normal levels by day 16. Total WBCs also reached a nadir on day 8, returning to normal by day 16. In the same timeframe cytarabine caused bone marrow ablation, with absolute neutrophil counts substantially reduced at day 8 and returning to normal by day 16. In conclusion SNS-595 has significant anti-tumor activity in hematologic xenografts, as well as significant ability to reversibly ablate murine bone marrow cells. These properties, combined with the good clinical safety profile observed in phase I patients, suggest that SNS-595 has the potential to demonstrate anti-tumor activity in patients with hematologic malignancies.