title: 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.
abstract: OBJECTIVE
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Wei-Gang
authors.initials: WG
authors.lastname: Tong
authors.forename: Rong
authors.initials: R
authors.lastname: Chen
authors.forename: William
authors.initials: W
authors.lastname: Plunkett
authors.forename: David
authors.initials: D
authors.lastname: Siegel
authors.forename: Rajni
authors.initials: R
authors.lastname: Sinha
authors.forename: R Donald
authors.initials: RD
authors.lastname: Harvey
authors.forename: Ashraf Z
authors.initials: AZ
authors.lastname: Badros
authors.forename: Leslie
authors.initials: L
authors.lastname: Popplewell
authors.forename: Steven
authors.initials: S
authors.lastname: Coutre
authors.forename: Judith A
authors.initials: JA
authors.lastname: Fox
authors.forename: Kristi
authors.initials: K
authors.lastname: Mahadocon
authors.forename: Tianling
authors.initials: T
authors.lastname: Chen
authors.forename: Peggy
authors.initials: P
authors.lastname: Kegley
authors.forename: Ute
authors.initials: U
authors.lastname: Hoch
authors.forename: William G
authors.initials: WG
authors.lastname: Wierda
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000032:analysis; D015331:Cohort Studies; D051357:Cyclin-Dependent Kinase 2 / Q000037:antagonists & inhibitors*; D042863:Cyclin-Dependent Kinase 9 / Q000037:antagonists & inhibitors*; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010080:Oxazoles / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D015996:Survival Rate; D013844:Thiazoles / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D014018:Tissue Distribution; D016896:Treatment Outcome; D000095043:Cyclin-Dependent Kinase-Activating Kinase
chemical_list: D014408:Biomarkers, Tumor; C484864:N-(5-(((5-(1,1-dimethylethyl)-2-oxazolyl)methyl)thio)-2-thiazolyl)-4-piperidinecarboxamide; D010080:Oxazoles; D013844:Thiazoles; C495894:CDK2 protein, human; C467969:CDK9 protein, human; D051357:Cyclin-Dependent Kinase 2; D042863:Cyclin-Dependent Kinase 9; D018844:Cyclin-Dependent Kinases; D000095043:Cyclin-Dependent Kinase-Activating Kinase; C000722416:CDK7 protein, human