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.
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.
Tong
Wei-Gang
WG
The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
Chen
Rong
R
Plunkett
William
W
Siegel
David
D
Sinha
Rajni
R
Harvey
R Donald
RD
Badros
Ashraf Z
AZ
Popplewell
Leslie
L
Coutre
Steven
S
Fox
Judith A
JA
Mahadocon
Kristi
K
Chen
Tianling
T
Kegley
Peggy
P
Hoch
Ute
U
Wierda
William G
WG
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
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