Original Article | Published:

Chronic Lymphocytic Leukemia

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

Leukemia volume 29, pages 15241529 (2015) | Download Citation

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 × 109 /l. Five separate dose levels (5 mg/m2, 7 mg/m2, 10 mg/m2, 14 mg/m2 and 17 mg/m2) 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/m2 dose (tumor lysis syndrome (TLS) and pneumonia). The phase II expansion occurred at 14 mg/m2 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.

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Acknowledgements

We wish to thank the patients who participated in this trial and their families who supported them. Additionally, we wish to thank the CTU and CTPL staff and leadership for supporting this trial. This work was supported by Specialized Center of Research from the Leukemia and Lymphoma Society, K12 CA133250, P50-CA140158, P01 CA95426, P01 CA8153 and P01 CA101956 from the National Cancer Institute, and The D. Warren Brown Foundation, Four Winds Foundation, Mr. and Mrs. Michael Thomas, and Harry Mangurian Foundation. This study was supported by Merck & Co., Inc.

Author Contributions

JF, RB and JCB designed the study, monitored toxicity, assessed response and drafted the first version of the paper. JJ, LA, KM and MG enrolled patients, reviewed drafts of the manuscript and approved the final version; AJJ, JH, EM, HZ, YZ and KS contributed to the performance of study, laboratory and pharmacodynamic studies, reviewed drafts of the manuscript and approved the final version.

Author information

Author notes

    • R Bannerji
    •  & J C Byrd

    These authors contributed equally to this work.

Affiliations

  1. Division of Hematology and Oncology, Department of Internal Medicine, Comprehensive Cancer Center at The Ohio State University, Columbus, OH, USA

    • J Flynn
    • , J Jones
    • , A J Johnson
    • , L Andritsos
    • , K Maddocks
    • , S Jaglowski
    • , J Hessler
    • , M R Grever
    •  & J C Byrd
  2. Division of Medicinal Chemistry, College of Pharmacy, The Ohio State University, Columbus, OH, USA

    • A J Johnson
    •  & J C Byrd
  3. Merck & Co., Inc., Oncology Clinical Research, Whitehouse Station, NJ, USA

    • E Im
    • , H Zhou
    • , Y Zhu
    • , D Zhang
    • , K Small
    •  & R Bannerji
  4. Rutgers Cancer Institute of New Jersey and Robert Wood Johnson Medical School, New Brunswick, NJ, USA

    • R Bannerji

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Competing interests

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

Corresponding authors

Correspondence to J Flynn or J C Byrd.

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DOI

https://doi.org/10.1038/leu.2015.31

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