Phase I trial of volasertib, a Polo-like kinase inhibitor, plus platinum agents in solid tumors: safety, pharmacokinetics and activity

Summary: Background This trial evaluated the maximum tolerated dose (MTD), safety, pharmacokinetics, and activity of volasertib, a selective Polo-like kinase 1 inhibitor that induces mitotic arrest and apoptosis, combined with cisplatin or carboplatin in patients with advanced/metastatic solid tumors (NCT00969761; 1230.6). Methods Sequential patient cohorts (3+3 dose-escalation design) received a single infusion of volasertib (100-350 mg) with cisplatin (60-100 mg/m2) or carboplatin (area under the concentration versus time curve [AUC]4-AUC6) on day 1 every 3 weeks for up to six cycles. Sixty-one patients received volasertib/cisplatin (n=30) or volasertib/carboplatin (n=31) for a median of 3.5 (range, 1-6) and 2.0 (range, 1-6) treatment cycles, respectively. Results The most common cycle 1 dose-limiting toxicities (DLTs) were thrombocytopenia, neutropenia and fatigue. MTDs (based on cycle 1 DLTs) were determined to be volasertib 300 mg plus cisplatin 100 mg/m2 and volasertib 300 mg plus carboplatin AUC6. Co-administration did not affect the pharmacokinetics of each drug. Partial responses were observed in two patients in each arm. Stable disease was achieved in 11 and six patients treated with volasertib/cisplatin and volasertib/carboplatin, respectively. Conclusions Volasertib plus cisplatin or carboplatin at full single-agent doses was generally manageable and demonstrated activity in heavily pretreated patients with advanced solid tumors.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Semi-mechanistic population pharmacokinetic/pharmacodynamic model for neutropenia following therapy with the Plk-1 inhibitor BI 2536 and its application in clinical development

International audienc

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

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.Clinical Trial, Phase IJournal ArticleResearch Support, Non-U.S. Gov'tSCOPUS: ar.jinfo:eu-repo/semantics/publishe

Localization of the Genes Encoding the Melanocortin-2 (Adrenocorticotropic Hormone) and Melanocortin-3 Receptors to Chromosomes 18p11.2 and 20q13.2-q13.3 by Fluorescence in Situ Hybridization

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/30538/1/0000171.pd

Phase I trial of the polo-like kinase (Plk) inhibitor volasertib (BI 6727) combined with cisplatin or carboplatin in patients with advanced solid tumors

status: publishe

Multicentric parallel phase II trial of the polo-like kinase 1 inhibitor BI 2536 in patients with advanced head and neck cancer, breast cancer, ovarian cancer, soft tissue sarcoma and melanoma : the first protocol of the European Organization for Research and Treatment of Cancer (EORTC) Network Of Core Institutes (NOCI)

Aims: BI 2536 is a selective and potent small-molecule inhibitor of polo-like kinase 1. We performed a multi-centre, multi-tumour phase II trial to investigate the efficacy, safety and pharmacokinetics of BI 2536 in five solid tumour types. Patients and methods: Patients with advanced head and neck, breast and ovarian cancer, soft tissue sarcoma and melanoma were selected according to protocol-defined general and tumour-specific criteria. They were >= 18 years old, had a good performance status, adequate bone marrow, renal and liver function, measurable progressive disease and had completed other relevant systemic treatments >4 weeks ago. BI 2536 200-250 mg was given intravenously on day 1 every 3 weeks until intolerance, progression or refusal. The study was based on a Simon two-stage design, with 12 patients entering in stage 1 and additional 25 patients to be entered in case of at least one response in the first stage. The rate of objective responses (RECIST criteria) was chosen as primary end-point. Results: Seventy six patients were included, 71 started treatment and received a median number of two cycles (four in ovarian cancer). Frequent grade 3-4 adverse events were neutropaenia (81.6%), thrombocytopaenia (19.7%), febrile neutropaenia (19.7%), anaemia (15.5%) and pain (9.9%). We did not observe confirmed objective responses. All cohorts were closed after the entry of 14-15 eligible non-responding patients. Pharmacokinetic analyses revealed multi-compartmental behaviour and a rapid distribution of BI 2536. Conclusions: BI 2536 showed limited antitumour activity according to the design of this trial in five different tumour types. Derivatives of BI 2536 with a more favourable pharmacological profile are currently explored further in prospective studies. (C) 2010 Elsevier Ltd. All rights reserved