A first-in-human, phase 1, dose-escalation study of dinaciclib, a novel cyclin-dependent kinase inhibitor, administered weekly in subjects with advanced malignancies

John J Nemunaitis, Karen A Small, Paul Kirschmeier, Da Zhang, Yali Zhu, Ying-Ming Jou, Paul Statkevich, Siu-Long Yao, Rajat Bannerji, John J Nemunaitis, Karen A Small, Paul Kirschmeier, Da Zhang, Yali Zhu, Ying-Ming Jou, Paul Statkevich, Siu-Long Yao, Rajat Bannerji

Abstract

Background: Dinaciclib, a small-molecule, cyclin-dependent kinase inhibitor, inhibits cell cycle progression and proliferation in various tumor cell lines in vitro. We conducted an open-label, dose-escalation study to determine the safety, tolerability, and bioactivity of dinaciclib in adults with advanced malignancies.

Methods: Dinaciclib was administered starting at a dose of 0.33 mg/m2, as a 2-hour intravenous infusion once weekly for 3 weeks (on days 1, 8, and 15 of a 28-day cycle), to determine the maximum administered dose (MAD), dose-limiting toxicities (DLTs), recommended phase 2 dose (RP2D), and safety and tolerability. Pharmacodynamics of dinaciclib were assessed using an ex vivo phytohemagglutinin lymphocyte stimulation assay and immunohistochemistry staining for retinoblastoma protein phosphorylation in skin biopsies. Evidence of antitumor activity was assessed by sequential computed tomography imaging after every 2 treatment cycles.

Results: Forty-eight subjects with solid tumors were treated. The MAD was found to be 14 mg/m2 and the RP2D was determined to be 12 mg/m2; DLTs at the MAD included orthostatic hypotension and elevated uric acid. Forty-seven (98%) subjects reported adverse events (AEs) across all dose levels; the most common AEs were nausea, anemia, decreased appetite, and fatigue. Dinaciclib administered at the RP2D significantly inhibited lymphocyte proliferation, demonstrating a pharmacodynamic effect. Ten subjects treated at a variety of doses achieved prolonged stable disease for at least 4 treatment cycles.

Conclusions: Dinaciclib administered every week for 3 weeks (on days 1, 8, and 15 of a 28-day cycle) was generally safe and well tolerated. Initial bioactivity and observed disease stabilization support further evaluation of dinaciclib as a treatment option for patients with advanced solid malignancies.

Trial registration: ClinicalTrials.gov # NCT00871663.

Figures

Figure 1
Figure 1
Pharmacodynamic relationships following treatment with dinaciclib. Relationship between percentage of bromodeoxyuridine uptake (relative to baseline) and dinaciclib plasma concentration (A), and best percentage change in maximum standard uptake value (SUVmax) determined by PET/CT scan (B) for subjects administered 0.33 to 14.0 mg/m2 doses of dinaciclib.
Figure 2
Figure 2
Pharmacokinetics of dinaciclib following 2-hour infusion at different doses. Mean dinaciclib concentration-time profiles following 2-hour IV infusion on day 1 of cycle 1 (A), comparison of individual AUC(I) on days 1 and 15 of cycle 1 (B), and dinaciclib plasma concentrations at the end of each 2-hour infusion (C) (on days 1, 8, and 15 of cycle 1 and on day 1 of cycle 2) for subjects administered dinaciclib at 0.33 mg/m2 to 14.0 mg/m2. For AUC(l), lines connect day 1 and day 15 values for subjects with data on both days.

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