Abstract
Purpose
Dinaciclib is a novel selective inhibitor of cyclin-dependent kinase (CDK)1, CDK2, CDK5, and CDK9. We conducted a phase I study to investigate the effects of dinaciclib when administered with rituximab.
Methods
In this phase I nonrandomized dose-escalation 3 + 3 trial, patients with relapsed/refractory chronic lymphocytic leukemia (CLL) were treated with dinaciclib and rituximab. Dinaciclib was administered intravenously (IV) over 2 h on days 1, 8 and 15 in cycles 2–13 (28-day cycles). Rituximab 375 mg/m2 was administered IV on days 1, 8, 15 and 22 in cycle 1 (28-day cycle) and on day 1 during cycle 3–13. Rituximab was not administered in cycle 2. Rituximab and dinaciclib were given alone in cycles 1 and 2, respectively, and in combination in cycles 3–13. Primary objectives included determination of the recommended phase II dose of dinaciclib and evaluation of pharmacokinetics (PK) when administered with rituximab.
Results
Five patients completed the study due to early termination. All presented with drug-related adverse events (AEs), but no dose-limiting toxicities were observed. The most commonly observed toxicities included hematological, digestive and metabolic AEs. However, no tumor lysis syndrome has been reported in the study. Four patients achieved stable disease, and one patient achieved complete response according to 2008 iwCLL criteria at cycle 3. PK samples were collected from 5 patients, and no obvious interaction between dinaciclib and rituximab was observed.
Conclusions
Limited data from this study shows dinaciclib in combination with rituximab was well tolerated and revealed encouraging clinical activity in relapsed/refractory CLL patients.
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Acknowledgments
The authors would like to thank Dr. Jérôme Couturier (Institut Curie, Paris, France), Pr. Frédéric Davi (Hôpital Pitié-Salpétrière, Paris, France), Dr. Claire Mathiot (Institut Curie, Paris, France), Dr. Vincent Servois (Institut Curie, Paris, France), for their contributions to biological and radiological assessments of the study and Kristen Lewis of Merck & Co., Inc., Whitehouse Station, NJ for editorial assistance. The study was sponsored by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. (Whitehouse Station, NJ).
Conflict of interest
CF, MG, CE, MZ, MPS and CLT have no conflicts of interest to disclose. KS, EI, NS, DZ and HZ are current or former employees of Merck & Co., Inc., Whitehouse Station, NJ and may own stock/stock options in the company.
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Fabre, C., Gobbi, M., Ezzili, C. et al. Clinical study of the novel cyclin-dependent kinase inhibitor dinaciclib in combination with rituximab in relapsed/refractory chronic lymphocytic leukemia patients. Cancer Chemother Pharmacol 74, 1057–1064 (2014). https://doi.org/10.1007/s00280-014-2583-9
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DOI: https://doi.org/10.1007/s00280-014-2583-9