title: Dinaciclib is a novel cyclin-dependent kinase inhibitor with significant clinical activity in relapsed and refractory chronic lymphocytic leukemia.
abstract: 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.
authors.affiliation: Division of Hematology and Oncology, Department of Internal Medicine, Comprehensive Cancer Center at The Ohio State University, Columbus, OH, USA.
authors.forename: J
authors.initials: J
authors.lastname: Flynn
authors.affiliation: Division of Hematology and Oncology, Department of Internal Medicine, Comprehensive Cancer Center at The Ohio State University, Columbus, OH, USA.
authors.forename: J
authors.initials: J
authors.lastname: Jones
authors.affiliation: 1] Division of Hematology and Oncology, Department of Internal Medicine, Comprehensive Cancer Center at The Ohio State University, Columbus, OH, USA [2] Division of Medicinal Chemistry, College of Pharmacy, The Ohio State University, Columbus, OH, USA.
authors.forename: A J
authors.initials: AJ
authors.lastname: Johnson
authors.affiliation: Division of Hematology and Oncology, Department of Internal Medicine, Comprehensive Cancer Center at The Ohio State University, Columbus, OH, USA.
authors.forename: L
authors.initials: L
authors.lastname: Andritsos
authors.affiliation: Division of Hematology and Oncology, Department of Internal Medicine, Comprehensive Cancer Center at The Ohio State University, Columbus, OH, USA.
authors.forename: K
authors.initials: K
authors.lastname: Maddocks
authors.affiliation: Division of Hematology and Oncology, Department of Internal Medicine, Comprehensive Cancer Center at The Ohio State University, Columbus, OH, USA.
authors.forename: S
authors.initials: S
authors.lastname: Jaglowski
authors.affiliation: Division of Hematology and Oncology, Department of Internal Medicine, Comprehensive Cancer Center at The Ohio State University, Columbus, OH, USA.
authors.forename: J
authors.initials: J
authors.lastname: Hessler
authors.affiliation: Division of Hematology and Oncology, Department of Internal Medicine, Comprehensive Cancer Center at The Ohio State University, Columbus, OH, USA.
authors.forename: M R
authors.initials: MR
authors.lastname: Grever
authors.affiliation: Merck & Co., Inc., Oncology Clinical Research, Whitehouse Station, NJ, USA.
authors.forename: E
authors.initials: E
authors.lastname: Im
authors.affiliation: Merck & Co., Inc., Oncology Clinical Research, Whitehouse Station, NJ, USA.
authors.forename: H
authors.initials: H
authors.lastname: Zhou
authors.affiliation: Merck & Co., Inc., Oncology Clinical Research, Whitehouse Station, NJ, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Merck & Co., Inc., Oncology Clinical Research, Whitehouse Station, NJ, USA.
authors.forename: D
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Merck & Co., Inc., Oncology Clinical Research, Whitehouse Station, NJ, USA.
authors.forename: K
authors.initials: K
authors.lastname: Small
authors.affiliation: 1] Merck & Co., Inc., Oncology Clinical Research, Whitehouse Station, NJ, USA [2] Rutgers Cancer Institute of New Jersey and Robert Wood Johnson Medical School, New Brunswick, NJ, USA.
authors.forename: R
authors.initials: R
authors.lastname: Bannerji
authors.affiliation: 1] Division of Hematology and Oncology, Department of Internal Medicine, Comprehensive Cancer Center at The Ohio State University, Columbus, OH, USA [2] Division of Medicinal Chemistry, College of Pharmacy, The Ohio State University, Columbus, OH, USA.
authors.forename: J C
authors.initials: JC
authors.lastname: Byrd
mesh_terms: D000328:Adult; D000368:Aged; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000493:pharmacokinetics / Q000627:therapeutic use*; D015331:Cohort Studies; D003497:Cyclic N-Oxides; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007212:Indolizines; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000473:pathology; D009367:Neoplasm Staging; D011379:Prognosis; D011726:Pyridinium Compounds / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016879:Salvage Therapy; D014018:Tissue Distribution
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; D003497:Cyclic N-Oxides; D007212:Indolizines; D011726:Pyridinium Compounds; C553669:dinaciclib; D018844:Cyclin-Dependent Kinases