Dinaciclib is a novel cyclin-dependent kinase inhibitor with significant clinical activity in relapsed and refractory chronic lymphocytic leukemia. Leukemia 2015 Jul;29(7):1524-9
Date
02/25/2015Pubmed ID
25708835Pubmed Central ID
PMC4551390DOI
10.1038/leu.2015.31Scopus ID
2-s2.0-84937022691 (requires institutional sign-in at Scopus site) 92 CitationsAbstract
Dinaciclib (SCH727965) is a selective CDKi chosen for clinical development based upon a favorable therapeutic index in cancer xenograft models. We performed a phase I dose escalation study of dinaciclib in relapsed and refractory chronic lymphocytic leukemia (CLL) patients with intact organ function and WBC<200 × 10(9) /l. Five separate dose levels (5 mg/m(2), 7 mg/m(2), 10 mg/m(2), 14 mg/m(2) and 17 mg/m(2)) were explored dosing on a weekly schedule × 3 with 1 week off (4-week cycles) using a standard 3+3 design with expansion cohorts to optimize safety. Fifty-two patients were enrolled with relapsed and refractory CLL. Escalation through cohorts occurred with two dose-limiting toxicity (DLTs) at the 17 mg/m(2) dose (tumor lysis syndrome (TLS) and pneumonia). The phase II expansion occurred at 14 mg/m(2) with 16 patients receiving this dose with one DLT (TLS). Additional stepped up dosing to the maximum tolerated dose was examined in 19 patients at this dose. Adverse events included cytopenias, transient laboratory abnormalities and TLS. Responses occurred in 28 (54%) of patients independent of del(17)(p13.1) with a median progression-free survival of 481 days. Dinaciclib is clinically active in relapsed CLL including those patients with high risk del(17)(p13.1) disease and warrants future study.
Author List
Flynn J, Jones J, Johnson AJ, Andritsos L, Maddocks K, Jaglowski S, Hessler J, Grever MR, Im E, Zhou H, Zhu Y, Zhang D, Small K, Bannerji R, Byrd JCAuthor
Samantha M. Jaglowski MD, MPH Professor in the Medicine department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AdultAged
Bridged Bicyclo Compounds, Heterocyclic
Cohort Studies
Cyclic N-Oxides
Cyclin-Dependent Kinases
Drug Resistance, Neoplasm
Female
Follow-Up Studies
Humans
Indolizines
Leukemia, Lymphocytic, Chronic, B-Cell
Male
Maximum Tolerated Dose
Middle Aged
Neoplasm Recurrence, Local
Neoplasm Staging
Prognosis
Pyridinium Compounds
Salvage Therapy
Tissue Distribution
