A phase I study of two administration schedules of the Polo-like kinase 1 inhibitor BI 2536 in patients with advanced solid tumors

Abstract

3069 Background: BI 2536 is a novel highly potent and selective inhibitor of the serine-threonine Polo-like kinase 1 (Plk1), a key regulator of cell cycle progression. Objectives of this trial were the assessment of the maximum tolerated dose (MTD), overall safety, pharmacokinetics and preliminary efficacy of BI 2536 given intravenously. Methods: Sequential cohorts of 3–6 patients (pat) with advanced or metastatic solid tumors received infusions of BI 2536 following a toxicity guided dose escalation design. In the first part of the trial, a single administration was given every 21 days (d1). After completion of accrual BI 2536 was administered on three consecutive days (d1–3) in a dose intensified schedule in additional patient cohorts. Further treatment courses were given in the absence of disease progression and after recovery of toxicity after a 3-week observation period. Results: Of the 52 entered patients a total of 40 pts were treated at doses of 25 (n=3), 50 (n=3), 100 (n=3), 200 (n=25) and 250 mg (n=6) in the d1 schedule. The MTD for the d1 schedule was defined at 200 mg. Dose limiting toxicity (DLT) consisted of neutropenic infection and occurred in 2/6 patients at 250 mg. Reversible CTCAE grade ≥ 3 neutropenia represented the main drug related toxicity with an incidence of 13/25 in the 200 mg and 5/6 in the 250 mg dose cohorts. Alopecia was reported in 20% of pat. Further common drug related adverse events (AE’s) consisted of nausea (38%), anorexia (25%) fatigue (18%), vomiting (18%) and mucositis (12%) and were mostly of mild to moderate intensity (CTCAE grade ≤ 2). PK analysis showed dose proportionality of Cmax and AUC0-∞ with a high clearance (∼ 1400 mL/min) and a high volume of distribution (∼ 1200 L). A correlation between exposure and neutropenia was observed. Patients were treated for up to 10 courses without evidence of accumulating toxicity. One partial response was observed in a patient with metastatic squamous cell head and neck cancer treated at 250 mg. The DLT was determined at 3x70 mg in the dose intensified schedule with the MTD still pending. Conclusion: In summary BI 2536 is a Plk1 inhibitor with a favorable safety and PK profile. Neutropenia as a mechanism-related toxicity indicates target inhibition in vivo. First signs of antitumor activity were observed. [Table: see text]