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

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BlankJournal of Clinical Oncology, Vol 28, No 18 (June 20), 2010: pp. 3015-3022

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

Wei-Gang Tong, Rong Chen, Plunkett, Siegel, Rajni Sinha, R.

Harvey, Ashraf Z. Badros, Popplewell, Coutre, Judith A. Fox,

Kristi Mahadocon, Tianling Chen, Peggy Kegley, Ute Hoch, G. Wierda

From the University of Texas M. D. Cancer Center, Houston, TX;

Hackensack University Medical Center, Hackensack, NJ; Emory University, Atlanta,

GA; University of land, Baltimore, MD; City of Hope, Duarte; Stanford

University, Stanford; and Sunesis Pharmaceuticals, South San Francisco; and

Nektar, San , CA.

Corresponding author: G. Wierda, MD, PhD, Department of Leukemia, Unit

428, The University of Texas M. D. Cancer Center, Houston, TX 77030;

e-mail: wwierda@... .

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.

W.G.W. is a Leukemia and Lymphoma Society Clinical Scholar.