A phase I repeated dose escalation study of the Polo-like kinase 1 inhibitor BI 2536 in patients with advanced solid tumours

Abstract

2038 Background: BI 2536 is a novel highly potent and selective inhibitor of the serine-threonine kinase polo-like kinase 1 (Plk1), which is a key regulator of cell cycle progression. Objectives of this trial were the assessment of the maximum tolerated dose (MTD), overall safety, pharmacokinetics and efficacy of BI 2536 given intravenously. Methods: Sequential cohorts of 3 to 6 patients (pts) with pretreated advanced or metastatic solid tumours received intravenous infusions of BI 2536 on days 1 and 8 of a 3-week treatment course following a toxicity guided dose escalation design. Further treatment courses were administered to pts in the absence of disease progression and if toxicity after a 3-week treatment course had resolved. Results: A total of 42 pts was treated at doses of 25 mg (n=3), 50 mg (n=3), 100 mg (n=22), 125 mg (n=5), 150 mg (n=6) and 200 mg (n=3). Reversible CTCAE grade ≥ 3 neutropenia in 14/42 pts represented the main drug related toxicity with an incidence of 3/5 in the 125 mg cohort, 4/6 in the 150 mg and 2/2 in the 200 mg dose cohorts. Dose limiting toxicity (DLT) was defined as drug related toxicity prohibiting administration of the day 8 dose of BI 2536 (hematologic: CTCAE ≥ 3 grade, non-hematologic toxicity: CTCAE ≥ 2). No DLT other than d8 neutropenia was observed. The MTD was defined at 100 mg for the given day 1 and 8 schedule. Further related adverse events (AE’s) were of mild to moderate intensity (CTCAE grade ≤ 2). There were no related AEs resulting in study discontinuation. Preliminary PK analysis showed dose proportionality of Cmax and AUC0-∞ with a high clearance (∼ 1500 mL/min) and a high volume of distribution (∼ 2000 L). No accumulation from d1 to d8 occurred. Patients were treated for up to 8 courses without evidence of accumulating toxicity. No objective responses were observed according to RECIST criteria in this heavily pretreated patient population. Conclusions: In summary BI 2536 is a Plk1 inhibitor with a favorable PK and safety profile at the tested dose and schedule. Neutropenia as a mechanism-related toxicity indicates target inhibition in vivo. [Table: see text]

The Efficacy and Safety of BI 2536, a Novel Plk-1 Inhibitor, in Patients with Stage IIIB/IV Non-small Cell Lung Cancer Who Had Relapsed after, or Failed, Chemotherapy: Results from an Open-Label, Randomized Phase II Clinical Trial

“…Data from the first in-man studies investigating the safety and pharmacokinetics (PKs) of BI 2536 in patients with advanced tumors demonstrated that BI 2536 was well tolerated, had a favorable PK profile, and showed potential antitumor activity. [12][13][14] When BI 2536 was administered as a single intravenous (iv) infusion or a daily infusion for 3 days, the maximum tolerated doses were 200 and 60 mg/d for the single iv infusion and the 3-consecutive-day infusion, respectively. 14 The most frequently observed adverse events (AEs) consisted of nausea, anorexia, fatigue, vomiting, and mucositis and were mostly of mild to moderate intensity.…”