Phase 1 safety, pharmacokinetic and pharmacodynamic study of the cyclin-dependent kinase inhibitor dinaciclib administered every three weeks in patients with advanced malignancies

Abstract

Background: Dinaciclib is a potent inhibitor of cell cycle and transcriptional cyclin-dependent kinases. This Phase 1 study evaluated the safety, tolerability and pharmacokinetics of various dosing schedules of dinaciclib in advanced solid tumour patients and assessed pharmacodynamic and preliminary anti-tumour activity.

Methods: In part 1, patients were enrolled in escalating cohorts of 2-h infusions administered once every 3 weeks, utilising an accelerated titration design until a recommended phase 2 dose (RP2D) was defined. In part 2, 8- and 24-h infusions were evaluated. Pharmacokinetic parameters were determined for all schedules. Pharmacodynamic effects were assessed with an ex vivo stimulated lymphocyte proliferation assay performed in whole blood.Effects of dinaciclib on retinoblastoma (Rb) phosphorylation and other CDK targets were evaluated in skin and tumour biopsies. In addition to tumour size, metabolic response was evaluated by 18F-fluorodeoxyglucose-positron emission tomography.

Results: Sixty-one patients were enrolled to parts 1 and 2. The RP2Ds were 50, 7.4 and 10.4 mg m-2 as 2- 8- and 24-hour infusions, respectively. Dose-limiting toxicities included pancytopenia, neutropenic fever, elevated transaminases, hyperuricemia and hypotension. Pharmacokinetics demonstrated rapid distribution and a short plasma half-life. Dinaciclib suppressed proliferation of stimulated lymphocytes. In skin and tumour biopsies, dinaciclib reduced Rb phosphorylation at CDK2 phospho-sites and modulated expression of cyclin D1 and p53, suggestive of CDK9 inhibition. Although there were no RECIST responses, eight patients had prolonged stable disease and received between 6 and 30 cycles. Early metabolic responses occurred.

Conclusions: Dinaciclib is tolerable at doses demonstrating target engagement in surrogate and tumour tissue.

Conflict of interest statement

JP, KAS, Y-MJ, PK, DZ, YZ, PS, and RB are present or former employees of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. JMC has served as a consultant for Agios, received grants from Merck & Co., Inc., and received travel/ accommodations from Roche and Bristol Myers Squibb (BMS). LRC has served as a consultant for Wilcox & Savage, Medical Science Affiliates, and Shook, Hardy & Bacon, and has given expert testimony for Shook, Hardy & Bacon, and has received royalties from Springer. SR has served as a member of the board for Perkin Elmer Inc., has received grants from BMS, and has received payment for lectures from BMS. GIS has received consultant fees from Lilly, Pfizer, G1 Therapuetics, Vertex, and EMD Serono. His institution has received grants from Lilly and Pfizer. An SRA related to immunohistochemical staining of skin and tumour biopsies, under which there will be payment from Merck to the Brigham and Women’s Hospital for work completed, will be executed in relation to this work. All other authors declare no conflict of interest.

Figures

Figure 1

Ex vivo assay of phytohemagglutinin (PHA)-stimulated lymphocyte proliferation. (A) BrdU incorporation of lymphocytes obtained from representative patients before and after 2-h dinaciclib infusions. BrdU=bromodeoxyuridine; D=day. (B) Relationship between percent BrdU uptake relative to baseline and dinaciclib plasma concentration in patients treated with 2-h infusions. Two additional samples with plasma concentrations >2000 and 3000 ng ml−1 demonstrated no BrdU uptake and are not plotted. Symbols indicate the time after the start of infusion when the sample was procured.

Figure 2

CDK targets assessed in skin biopsies of patients before and after intravenous infusions of dinaciclib>29.6 mg m−2. (A) Quantification of the percent decline in number of keratinocytes staining positively for expression of various forms of phosphorylated Rb, total Rb and Ki-67 in post- compared to pre-treatment samples. (B) Quantification of the percent decline or increase in number of keratinocytes staining positively for expression of p27Kip1, cyclin D1 and p53 in post- compared to pre-treatment samples. In (A) and (B), the number of paired samples analysed is indicated above or below the bar. ***P<0.0001; **P<0.01; *P<0.05 in paired t-tests. (C) Representative micrographs from pre- and post-treatment samples demonstrating reduced staining for Rb [pT356], relatively unchanged staining of total Rb and Rb [S807/S811] and increased staining of p53 in post-treatment samples.

Figure 3

CDK targets assessed in paired tumour biopsies from three patients with metastatic melanoma. Post-treatment biopsies were obtained within 24 h after the end of the infusion. (A) Quantification and representative micrographs from a patient treated with 50 mg m−2 over 2 h. Most notable changes in the post-treatment sample are reduced Rb [pT356], unchanged expression of other phospho-Rb forms, and increased expression of p27Kip1 and slight induction of p53. (B) Quantification and representative micrographs from a patient treatment with 29.6 mg m−2 over 2 h, with similar changes, including reduced Rb [pS795]. (C) Quantification and representative micrographs from a patient treated with 14.8 mg m−2 over 8 h, again demonstrating similar pharmacodynamic changes, most notably with reduced Rb [pT356] and Rb [pS795].