Phase I and Pharmacologic Study of SNS-032, a Potent and Selective Cdk2, 7, and 9 Inhibitor, in Patients With Advanced Chronic Lymphocytic Leukemia and Multiple Myeloma

• Type of Material: Article
• Authors: Wei-Gang Tong, Emory University; Rong Chen, University of Texas; William Plunkett; David Siegel; Rajni Sinha; R. Harvey; Ashraf Z. Badros; Leslie Popplewell; Steve Coutre; Judith A. Fox; Kristi Mahadocon; Tianling Chen; Peggy Kegley; Ute Hoch; William G. Wierda
• Language: English
• Date: 2010-06-20
• Publisher: American Society of Clinical Oncology
• Publication Version: Final Published Version
• Copyright Statement: © 2010 by American Society of Clinical Oncology
• Final Published Version (URL): http://dx.doi.org/10.1200/JCO.2009.26.1347
• Title of Journal or Parent Work: Journal of Clinical Oncology
• ISSN: 0732-183X
• Volume: 28
• Issue: 18
• Start Page: 3015
• End Page: 3022
• Grant/Funding Information: Research Funding: William Plunkett, Sunesis Pharmaceuticals; Leslie Popplewell, Sunesis Pharmaceuticals; Steven Coutre, Sunesis Pharmaceuticals; William G. Wierda, Bayer, Sanofi-Aventis, Abbott, GlaxoSmithKline, Sunesis Pharmaceuticals
• Keywords: ROSCOVITINE; 72-HOUR CONTINUOUS-INFUSION; MODULATORS; Oncology; Science & Technology; MCL-1; FLAVOPIRIDOL INDUCES APOPTOSIS; Life Sciences & Biomedicine; BCL-2; MECHANISM; ONCOLOGY; CELL-CYCLE; DEPENDENT KINASE INHIBITOR; CANCER-THERAPY
• Research Categories: Health Sciences, Oncology; Biology, Cell; Biology, Molecular

Abstract

Purpose: SNS-032 is a highly selective and potent inhibitor of cyclin-dependent kinases (Cdks) 2, 7, and 9, with in vitro growth inhibitory effects and ability to induce apoptosis in malignant B cells. A phase I dose-escalation study of SNS-032 was conducted to evaluate safety, pharmacokinetics, biomarkers of mechanism-based pharmacodynamic (PD) activity, and clinical efficacy. Patients and Methods: Parallel cohorts of previously treated patients with chronic lymphocytic leukemia (CLL) and multiple myeloma (MM) received SNS-032 as a loading dose followed by 6-hour infusion weekly for 3 weeks of each 4-week course. Results: There were 19 patients with CLL and 18 with MM treated. Tumor lysis syndrome was the dose-limiting toxicity (DLT) for CLL, the maximum-tolerated dose (MTD) was 75 mg/m2, and the most frequent grade 3 to 4 toxicity was myelosuppression. One patient with CLL had more than 50% reduction in measurable disease without improvement in hematologic parameters. Another patient with low tumor burden had stable disease for four courses. For patients with MM, no DLT was observed and MTD was not identified at up to 75 mg/m2, owing to early study closure. Two patients with MM had stable disease and one had normalization of spleen size with treatment. Biomarker analyses demonstrated mechanism-based PD activity with inhibition of Cdk7 and Cdk9, decreases in Mcl-1 and XIAP expression level, and associated CLL cell apoptosis. Conclusion: SNS-032 demonstrated mechanism-based target modulation and limited clinical activity in heavily pretreated patients with CLL and MM. Further single-agent, PD-based, dose and schedule modification is warranted to maximize clinical efficacy.