Clinical and laboratory studies of the novel cyclin-dependent kinase inhibitor dinaciclib (SCH 727965) in acute leukemias

Abstract

PurposeDinaciclib inhibits cyclin-dependent kinases 1, 2, 5, and 9 with a better therapeutic index than flavopiridol in preclinical studies. This study assessed the activity of dinaciclib in acute leukemia both in the clinic and in vitro.MethodsAdults with relapsed/refractory acute myeloid leukemia (n = 14) and acute lymphoid leukemia (n = 6) were treated with dinaciclib 50 mg/m2 given as a 2-h infusion every 21 days.ResultsMost patients had dramatic but transient reduction in circulating blasts; however, no remissions were achieved on this schedule. The most common toxicities were gastrointestinal, fatigue, transaminitis, and clinical and laboratory manifestations of tumor lysis syndrome, including one patient who died of acute renal failure. Dinaciclib pharmacokinetics showed rapid (2 h) achievement of maximum concentration and a short elimination/distribution phase. Pharmacodynamic studies demonstrated in vivo inhibition of Mcl-1 expression and induction of PARP cleavage in patients’ peripheral blood mononuclear cells 4 h after dinaciclib infusion, but the effects were lost by 24 h and did not correlate with clinical outcome. Correlative in vitro studies showed that prolonged exposures to dinaciclib, at clinically attainable concentrations, result in improved leukemia cell kill.ConclusionsWhile dinaciclib given as a 2-h bolus did not exhibit durable clinical activity, pharmacokinetic and pharmacodynamic data support the exploration of prolonged infusion schedules in future trials in patients with acute leukemias. Electronic supplementary materialThe online version of this article (doi:10.1007/s00280-013-2249-z) contains supplementary material, which is available to authorized users.

Dinaciclib, a Cyclin-Dependent Kinase Inhibitor Promotes Proteasomal Degradation of Mcl-1 and Enhances ABT-737-Mediated Cell Death in Malignant Human Glioma Cell Lines

“…Compared with flavopiridol, dinaciclib showed a superior therapeutic index in a preclinical setting (Parry et al, 2010). Preliminary pharmacokinetic data from clinical studies in solid tumors suggest that average dinaciclib concentrations of 82.3-184 nM can be achieved (Mita et al, 2014;Gojo et al, 2013). Using a large panel of glioma cell lines, we have demonstrated that CDK inhibitors effectively inhibit cell proliferation.…”

“…Parry et al (2010) also showed that dinaciclib inhibited cell proliferation and cell-cycle progression in multiple tumor cell lines across a broad range of tumor types with different genetic backgrounds and induced regression of established solid tumors in mouse models. Despite research advances, reports of randomized phase 2 trials of dinaciclib in solid tumors have been disappointing (Mita et al, 2014), with no significant response in patients with non-small cell lung cancer (Stephenson et al, 2014) or acute lymphoblastic leukemia (Gojo et al, 2013). In this study, we investigated the cellular responses to CDK inhibitors in a panel of glioma cancer cell lines.…”

“…Because we observed that the effects of this agent were almost entirely cytostatic rather than cytotoxic, we questioned whether the efficacy of dinaciclib could be enhanced by combining it with a second agent that tipped the balance in favor of apoptosis rather than cell-cycle arrest. Because Gojo et al (2013) demonstrated dinaciclib-induced in vivo inhibition of Mcl-1 expression in patients' peripheral blood mononuclear cells, we hypothesized that combining dinaciclib and ABT-737 would potentiate apoptosis induction in glioma. In this study, we demonstrated the potential benefit of combining the CDK inhibitor dinaciclib with the Bcl-2/BclxL antagonist ABT-737, and here we highlight the potential benefits of simultaneously targeting both survival pathways in patients with glioma.…”

Dinaciclib induces immunogenic cell death and enhances anti-PD1–mediated tumor suppression

“…In mice, the elimination of dinaciclib is even more rapid, with a half-life of less than 1 hour (48,58). In both humans and mice, the direct pharmacodynamic effects of dinaciclib, including inhibition of MCL1, induction of PARP cleavage, and inhibition of PHA-stimulated lymphocyte proliferation, are transient and correlate with plasma drug concentration (58,74,82). In our study, dinaciclib-dependent changes in type I IFN gene expression within the tumor were observed at 24 hours, but not 4 days after dosing (not shown).…”

New Strategies in the Treatment of Mantle Cell Lymphoma

“…PD0332991 is a specific inhibitor of CDK4 and CDK6, is generally well tolerated, and has shown clinical activity (57)(58)(59)(60). SCH727965 (dinaciclib), a novel inhibitor of CDK1, -2, -5, and -9, showed superior activity and an improved therapeutic index compared with flavopiridol in laboratory models of solid and hematologic malignancies (61,62) and was the subject of intense investigation in numerous clinical trials (63)(64)(65). However, preliminary data did not show a dramatic response to these CDK inhibitors, suggesting that other deregulated pathways are contributing to the growth and survival advantages of aggressive MCL cells compared with normal cells (8,33,34).…”