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).
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.
Schöffski
Patrick
P
Department of General Medical Oncology, University Hospitals Leuven, Laboratory of Experimental Oncology, Leuven Cancer Institute, Catholic University Leuven, Leuven, Belgium. patrick.schoffski@uzleuven.be
Blay
Jean-Yves
JY
De Greve
Jacques
J
Brain
Etienne
E
Machiels
Jean-Pascal
JP
Soria
Jean-Charles
JC
Sleijfer
Stefan
S
Wolter
Pascal
P
Ray-Coquard
Isabelle
I
Fontaine
Christel
C
Munzert
Gerd
G
Fritsch
Holger
H
Hanft
Gertraud
G
Aerts
Claire
C
Rapion
Jérome
J
Allgeier
Anouk
A
Bogaerts
Jan
J
Lacombe
Denis
D
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
D000970:Antineoplastic Agents; C518477:BI 2536; D011621:Pteridines