Elsevier

European Journal of Cancer

Volume 46, Issue 12, August 2010, Pages 2206-2215
European Journal of Cancer

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)

https://doi.org/10.1016/j.ejca.2010.03.039Get rights and content

Abstract

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.

Introduction

In 1991, the polo gene, encoding for an enzyme present in Drosophila melanogaster, was discovered and cloned. In Drosophila, mutations in polo were found to induce abnormal mitoses. In 1993, Clay and colleagues identified and cloned gene sequences in murine haematopoietic progenitor cells encoding for a protein kinase that shares extensive homology with the enzyme encoded by Drosophila’s polo gene. The mouse gene was called Plk. The protein encoded by Plk, polo-like kinase, belongs to a family of serine/threonine kinases that are involved in cell growth and differentiation in various species. In 1994, both human and murine cDNAs that were homologous to Drosophila’s polo gene and the related kinase were cloned. The human counterpart was named PLK. Polo-like kinases (PLKs) play a key role in processes such as cell division and checkpoint regulation of mitosis. About 80% of human tumours express high levels of PLK transcripts, while PLK mRNA is mostly absent in surrounding healthy tissues (reviewed in [1]). Overexpression of PLK is associated with poor prognosis in several tumour types and a lower overall survival rate. The overexpression of PLKs in human tumours, but not in healthy non-dividing cells, makes them an attractive, selective target for anticancer drug development.2, 3

PLK inhibitors interfere with different stages of mitosis such as centrosome maturation, spindle formation, chromosome separation and cytokinesis. They induce mitotic chaos and severely perturb cell cycle progression (‘Polo arrest’), eventually leading to cancer cell death. PLK1, the most extensively characterised member of the polo family, controls critical steps in the passage of cells through the M phase of the cell cycle, including initiation of entry into mitosis, centrosome separation necessary for the formation of a bipolar mitotic spindle, metaphase to anaphase transition and mitotic exit and onset of cell division (Fig. 1A).1 PLK inhibitors act on the mitotic spindle in a completely different manner than the established anticancer agents such as vinca alkaloids or taxanes, which directly bind to structural components of the spindle, but do not interfere with the regulation of the mitotic process (Fig. 1B).

BI 2536 is a highly selective and potent small molecule PLK1 inhibitor.4 The free base (BI 2536 BS) is used as an intravenous formulation. The molecular potency of BI 2536 is in the low nanomolar range. More than 45 kinases tested in parallel with PLK1 were not inhibited. In a panel of tumour cell lines, activity was not dependent on cellular origin or molecular phenotype. Three clinical phase I dose-ranging studies have been performed with BI 2536, testing four different 3-weekly schedules.5, 6, 7 BI 2536 was administered either on day 1, days 1 and 8, days 1, 2 and 3 or as a 24-h infusion on day 1. BI 2536 was generally well tolerated, with a MTD defined in two independent phase I studies as once-weekly 200 mg/cycle or twice-weekly 100 mg/cycle. The dose-limiting toxicities (DLTs) were reversible and non-cumulative neutropaenia and thrombocytopaenia, as expected from preclinical testing of this compound. Other related adverse events were of mild to moderate intensity. BI 2536 had a favourable, dose-dependent safety profile. A pharmacokinetic (PK) analysis showed dose-proportional maximum plasma concentrations and total exposure, with a terminal elimination half-life of about 17–34 h. BI 2536 had a high total clearance from plasma and a high volume of distribution. Hints of antitumour activity were observed in the heavily pre-treated patient population involved in the phase I programme, providing the rationale for further clinical development of BI 2536 in various solid tumour indications.

The aim of the current multi-tumour phase II protocol was to screen for activity and evaluate the safety of BI 2536 in patients with various well-defined advanced cancers. The day 1 every 3 week schedule was chosen as a safe, feasible and tolerable regimen. The primary end-point was to assess the confirmed objective response (OR) rate (complete and partial responses) as defined by RECIST.8 The study also assessed the duration of response in responding patients, progression-free survival and overall survival. The safety was documented by CTCAE version 3.0. The objective of the PK analysis was to describe the plasma concentration time-course following administration of a single administration of BI 2536.

Section snippets

Trial design

This trial was performed as a set of parallel phase II investigations in five different solid tumours combined in one protocol. Each of the phase II cohorts had a similar design with OR as the primary end-point. The trial was a multi-centre, open-label, non-randomised study. Patients were registered at the EORTC Headquarters prior to the start of treatment after signing of informed consent and verification of eligibility. The study included a screening visit, consecutive study assessments and a

Patient characteristics

Of the 71 patients treated in this trial, 27 (38.0%) were male and 44 (62.0%) were female. The median age was 58 years and their median weight was 67 kg. Demographic data are summarised in Table 1. Sixty-one patients (85.9%) had previously undergone surgery for their tumour. The most common therapy combinations comprised surgery with chemotherapy (25 patients; 35.2%); surgery with chemotherapy, radiotherapy and other therapies (13 patients; 18.3%); and surgery with chemotherapy and radiotherapy

Discussion

This study aimed to assess the efficacy of BI 2536 in five parallel patient cohorts, to characterise antitumour activity of the novel compound in head and neck cancer, breast cancer and ovarian cancer, soft tissue sarcoma and melanoma. The end-point was the determination of the objective response rate, but none of the first 14–15 evaluable patients per tumour type experienced a complete or partial response during the conduct of the trial. Consequently, all strata were closed after completion of

Conflict of interest statement

Patrick Schöffski: Advisory Board Member Boehringer Ingelheim Pharma; Jacques De Grève: unrestricted research grant 2009 Boehringer Ingelheim; Gerd Munzert, Holger Fritsch, Gertraud Hanft: Employee of Boehringer Ingelheim Pharma GmbH and Co. KG; and No conflict of interest for other authors.

Acknowledgments

Support: Boehringer Ingelheim Pharma GmbH & Co KG was the legal sponsor of this trial (EudraCT: 2006-004529-27), which was performed within the European Organization for Research and Treatment of Cancer (EORTC) Network Of Core Institutes (NOCI) plus selected additional sites.

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