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.

CDK2-mediated site-specific phosphorylation of EZH2 drives and maintains triple-negative breast cancer

“…The 4T1 tumor-bearing mice were treated with either EZP6438 (34 mg kg −1 ; equivalent to 102.3 mg m −2 in human) or dinaciclib (8 mg kg −1 ; equivalent to 24 mg m −2 in human). The doses of EZH2i and CDK2i chosen were much lower than those of recommended phase 2 dose (RP2D: EPZ-6438, 800 mg m −2 ; dinaciclib, 50 mg m −2 ) 30,31 . For combination therapy, mice were administered tamoxifen after 3 days of CDKi or EZH2i monotherapy.…”

“…Dinaciclib has demonstrated antitumor activity in leukemia and other types of solid tumors as a single agent with a safety profile in patients 19,20 . Phase I clinical trial reports indicated that patients treated with dinaciclib at high dose (>29.6 mg m −2 , equivalent to >9.84 mg kg −1 in mice) experienced dose-dependent adverse effects 30,31 . To rule out the possible toxicity of dinaciclib (8 mg kg −1 ) combined with tamoxifen (4 mg kg −1 ) in mice for longer treatment schedule (21 day in Fig.…”

Potent Activity of Composite Cyclin Dependent Kinase Inhibition against Hepatocellular Carcinoma

“…One of the concerns in the development of CDK inhibitors in the treatment of HCC is bone marrow suppression because many patients with HCC have preexisting cytopenia due to liver cirrhosis and splenomegaly. Although neutropenia was common in patients who received triweekly dosing of dinaciclib [28,36], a weekly schedule of dinaciclib was shown to be more tolerable [30]. In addition, our results revealed that CDKs 1 and 9, especially CDK9, might be the most crucial CDKs in HCC treatment.…”

Old Drugs for a New Virus: Repurposed Approaches for Combating COVID-19

“… 54 However, serious hematological toxicities may limit the use of dinaciclib as an antiviral drug. 58 …”