Dinaciclib is a novel cyclin-dependent kinase inhibitor with significant clinical activity in relapsed and refractory chronic lymphocytic leukemia

J Flynn, J Jones, A J Johnson, L Andritsos, K Maddocks, S Jaglowski, J Hessler, M R Grever, E Im, H Zhou, Y Zhu, D Zhang, K Small, R Bannerji, J C Byrd, J Flynn, J Jones, A J Johnson, L Andritsos, K Maddocks, S Jaglowski, J Hessler, M R Grever, E Im, H Zhou, Y Zhu, D Zhang, K Small, R Bannerji, J C Byrd

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.

Conflict of interest statement

Conflict-of-interest disclosure: EI, HZ, YZ, KS are employees of Merck & Co., Inc. RB was an employee of Merck & Co., Inc., at the time of this study.

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