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 - PubMed (original) (raw)

Clinical Trial

. 2010 Jun 20;28(18):3015-22.

doi: 10.1200/JCO.2009.26.1347. Epub 2010 May 17.

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

Affiliations

Clinical Trial

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 et al. J Clin Oncol. 2010.

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/m(2), 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/m(2), 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.

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Conflict of interest statement

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

Figures

Fig 1.

Fig 1.

SNS-032 plasma concentration-time profiles. Mean pharmacokinetic profiles for all dose cohorts from patients with multiple myeloma and chronic lymphocytic leukemia are shown. Filled circles, 15 mg/m2, n = 3; open circles, 22 mg/m2, n = 2; filled inverted triangles, 33 mg/m2, n = 8; open triangles, 50 mg/m2, n = 7; filled squares, 75 mg/m2, n = 10; open squares, 100 mg/m2, n = 2; solid line, concentration that inhibits 90%.

Fig 2.

Fig 2.

Target modulation after SNS-032 infusion in patients with chronic lymphocytic leukemia. (A) Representative immunoblots from a patient treated with 75 mg/m2 of SNS-032. The ratio indicates the densitometry analysis between pPol II-Ser2 or pPol II-Ser5 and total Pol II, normalized to predose controls. (B) Representative immunoblots showing the protein levels of Mcl-1, XIAP, and Bcl-2 after SNS-032 infusion. The ratio indicates the densitometry analysis between Mcl-1, XIAP or Bcl-2, and actin, normalized to predose controls. Cleavage of poly (adenosine diphosphate–ribose) polymerase (PARP; arrow) was used as an indicator of apoptosis. (C) The summarized quantitations of phosphorylation of Ser2 at the C-terminal domain of RNA Pol II and protein levels of Mcl-1 and Bcl-2 for two patients treated with 75 mg/m2 (closed symbols) and two patients treated with 100 mg/m2 (open symbols) of SNS-032.

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