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.

• Authors: Monica M Mita, Alain C Mita, Jennifer L Moseley, Jennifer Poon, Karen A Small, Ying-Ming Jou, Paul Kirschmeier, Da Zhang, Yali Zhu, Paul Statkevich, Kamelesh K Sankhala, John Sarantopoulos, James M Cleary, Lucian R Chirieac, Scott J Rodig, Rajat Bannerji, Geoffrey I Shapiro
• Journal: British journal of cancer (Br J Cancer) Vol. 117 Issue 9 Pg. 1258-1268 (Oct 24 2017) ISSN: 1532-1827 [Electronic] England
• PMID: 28859059 (Publication Type: Clinical Trial, Phase I, Journal Article)

Chemical References

• Bridged Bicyclo Compounds, Heterocyclic
• Cyclic N-Oxides
• Indolizines
• Protein Kinase Inhibitors
• Pyridinium Compounds
• dinaciclib
• Cyclin-Dependent Kinases

Topics

• Adolescent
• Adult
• Aged
• Bridged Bicyclo Compounds, Heterocyclic (pharmacokinetics, therapeutic use)
• Cyclic N-Oxides
• Cyclin-Dependent Kinases (antagonists & inhibitors)
• Drug Administration Schedule
• Female
• Follow-Up Studies
• Humans
• Indolizines
• Male
• Middle Aged
• Neoplasm Staging
• Neoplasms (drug therapy, pathology)
• Prognosis
• Protein Kinase Inhibitors (pharmacokinetics, therapeutic use)
• Pyridinium Compounds (pharmacokinetics, therapeutic use)
• Tissue Distribution
• Young Adult