About this item:

539 Views | 511 Downloads

Author Notes:

Corresponding author: William G. Wierda, MD, PhD, Department of Leukemia, Unit 428, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030; e-mail: wwierda@mdanderson.org.

Conception and design: Rong Chen, William Plunkett, Steven Coutre, Ute Hoch, William G. Wierda

Provision of study materials or patients: David Siegel, R. Donald Harvey, Ashraf Z. Badros, Leslie Popplewell, Steven Coutre, William G. Wierda

Collection and assembly of data: Wei-Gang Tong, Rong Chen, William Plunkett, David Siegel, R. Donald Harvey, Peggy Kegley, William G. Wierda

Data analysis and interpretation: Wei-Gang Tong, Rong Chen, William Plunkett, Judith A. Fox, Kristi Mahadocon, Tianling Chen, Ute Hoch, William G. Wierda

Manuscript writing: Wei-Gang Tong, Rong Chen, William Plunkett, Rajni Sinha, Judith A. Fox, William G. Wierda

Final approval of manuscript: Wei-Gang Tong, Rong Chen, William Plunkett, David Siegel, Rajni Sinha, R. Donald Harvey, Ashraf Z. Badros, Leslie Popplewell, Steven Coutre, Judith A. Fox, Kristi Mahadocon, Tianling Chen, Peggy Kegley, Ute Hoch, William G. Wierda

Author's affiliation not clear in article.

For a detailed description of the conflict disclosures please see full article

Subjects:

Research Funding:

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:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Oncology
  • ONCOLOGY
  • DEPENDENT KINASE INHIBITOR
  • FLAVOPIRIDOL INDUCES APOPTOSIS
  • 72-HOUR CONTINUOUS-INFUSION
  • CANCER-THERAPY
  • CELL-CYCLE
  • BCL-2
  • MCL-1
  • ROSCOVITINE
  • MODULATORS
  • MECHANISM

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

Show all authors Show less authors

Tools:

Journal Title:

Journal of Clinical Oncology

Volume:

Volume 28, Number 18

Publisher:

, Pages 3015-3022

Type of Work:

Article | Final Publisher PDF

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.

Copyright information:

© 2010 by American Society of Clinical Oncology

Export to EndNote