A phase I, dose-escalation study of the novel Polo-like kinase inhibitor volasertib (BI 6727) in patients with advanced solid tumours

作者：Schoffski Patrick^*; Awada Ahmad; Dumez Herlinde; Gil Thierry; Bartholomeus Sylvie; Wolter Pascal; Taton Martine; Fritsch Holger; Glomb Patricia; Munzert Gerd

来源：European Journal of Cancer, 2012, 48(2): 179-186.

DOI：10.1016/j.ejca.2011.11.001

• Polo-like kinase (Plk) inhibitor
• Phase I
• Solid tumours
• Volasertib (BI 6727)
• Dose escalation

Background: Volasertib (BI 6727) is a potent and selective cell-cycle kinase inhibitor that induces mitotic arrest and apoptosis by targeting Polo-like kinase (Plk). This phase I dose-escalation study evaluated the maximum tolerated dose (MTD) of volasertib, safety and efficacy, and pharmacokinetic (PK) parameters.
Methods: This trial followed an open-label, toxicity-guided dose-titration design. Patients with progressive advanced or metastatic solid tumours received a single 1-h infusion of volasertib every 3 weeks. A total of 65 patients were treated at doses of 12-450 mg.
Results: Reversible haematological toxicity was the main side-effect; thrombocytopenia, neutropenia, and febrile neutropenia constituting the main dose-limiting events. Anaemia (all grades 22%; grade 3:8%), neutropenia (15%; grade 3/4:14%), fatigue (15%; grade 3:2%), and thrombocytopenia (14%; grade 3/4:14%) were the most frequent drug-related adverse events. The MTD was 400 mg; however, 300 mg was the recommended dose for further development based on overall tolerability. Three patients achieved confirmed partial response. Stable disease as best response was reported in 40% of patients. Two patients remained progression free for >1 year. PK analysis showed no indication of deviation from 'dose-linear PK' behaviour, a large volume of distribution (>4000 l), moderate clearance and a long half-life (similar to 111 h).
Conclusion: This first-in-man trial demonstrated a favourable PK profile of volasertib, with manageable toxicities. As expected, the most common events were haematological. Encouraging preliminary antitumour activity has been observed, supporting Plk inhibition as a therapeutic approach. Clinical development of volasertib in phase II monotherapy and combination trials is ongoing.

• 出版日期2012-1