A phase I, dose-escalation study of the novel Polo-like kinase inhibitor volasertib (BI 6727) in patients with advanced solid tumours
| Autor: | Patrick Schöffski, Holger Fritsch, Patricia Glomb, Ahmad Awada, Pascal Wolter, Gerd Munzert, Herlinde Dumez, S. Bartholomeus, M. Taton, Thierry Gil |
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| Rok vydání: | 2012 |
| Předmět: |
Adult
Male Oncology Cancer Research medicine.medical_specialty Antineoplastic Agents Neutropenia Pharmacology Cohort Studies Young Adult chemistry.chemical_compound Pharmacokinetics Neoplasms Internal medicine Humans Medicine Adverse effect Protein Kinase Inhibitors Aged Volume of distribution Dose-Response Relationship Drug business.industry Pteridines Volasertib Middle Aged medicine.disease Clinical trial chemistry Tolerability Female business Febrile neutropenia Half-Life |
| Zdroj: | European Journal of Cancer. 48:179-186 |
| ISSN: | 0959-8049 |
| Popis: | 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 (∼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. |
| Databáze: | OpenAIRE |
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