title: 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).
abstract: OBJECTIVE
  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.
  
  
  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 18years old, had a good performance status, adequate bone marrow, renal and liver function, measurable progressive disease and had completed other relevant systemic treatments >4weeks ago. BI 2536 200-250mg 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.
authors.affiliation: Department of General Medical Oncology, University Hospitals Leuven, Laboratory of Experimental Oncology, Leuven Cancer Institute, Catholic University Leuven, Leuven, Belgium. patrick.schoffski@uzleuven.be
authors.forename: Patrick
authors.initials: P
authors.lastname: Schöffski
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Blay
authors.forename: Jacques
authors.initials: J
authors.lastname: De Greve
authors.forename: Etienne
authors.initials: E
authors.lastname: Brain
authors.forename: Jean-Pascal
authors.initials: JP
authors.lastname: Machiels
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Soria
authors.forename: Stefan
authors.initials: S
authors.lastname: Sleijfer
authors.forename: Pascal
authors.initials: P
authors.lastname: Wolter
authors.forename: Isabelle
authors.initials: I
authors.lastname: Ray-Coquard
authors.forename: Christel
authors.initials: C
authors.lastname: Fontaine
authors.forename: Gerd
authors.initials: G
authors.lastname: Munzert
authors.forename: Holger
authors.initials: H
authors.lastname: Fritsch
authors.forename: Gertraud
authors.initials: G
authors.lastname: Hanft
authors.forename: Claire
authors.initials: C
authors.lastname: Aerts
authors.forename: Jérome
authors.initials: J
authors.lastname: Rapion
authors.forename: Anouk
authors.initials: A
authors.lastname: Allgeier
authors.forename: Jan
authors.initials: J
authors.lastname: Bogaerts
authors.forename: Denis
authors.initials: D
authors.lastname: Lacombe
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism; D005240:Feasibility Studies; D005260:Female; D006258:Head and Neck Neoplasms / Q000188:drug therapy / Q000378:metabolism; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008545:Melanoma / Q000188:drug therapy / Q000378:metabolism; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000378:metabolism; D010349:Patient Compliance; D011621:Pteridines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D012509:Sarcoma / Q000188:drug therapy / Q000378:metabolism; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; C518477:BI 2536; D011621:Pteridines