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Journal of Thoracic Oncology:
doi: 10.1097/JTO.0b013e3181d95dd4
Original Articles

The Efficacy and Safety of BI 2536, a Novel Plk-1 Inhibitor, in Patients with Stage IIIB/IV Non-small Cell Lung Cancer Who Had Relapsed after, or Failed, Chemotherapy: Results from an Open-Label, Randomized Phase II Clinical Trial

Sebastian, Martin MD*; Reck, Martin MD†; Waller, Cornelius F. MD‡; Kortsik, Cornelius MD§; Frickhofen, Norbert MD∥; Schuler, Martin MD¶; Fritsch, Holger MD#; Gaschler-Markefski, Birgit PhD#; Hanft, Gertraud MD#; Munzert, Gerd MD#; von Pawel, Joachim MD**

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Author Information

*Department of Medicine III, Universitaetsmedizin, Mainz; †Department of Thoracic Oncology, Hospital Grosshansdorf, Grosshansdorf; ‡Department of Hematology/Oncology, University of Freiburg, Freiburg; §Department of Pulmonary Medicine, KKM, St. Hildegardis-Hospital, Mainz; ∥Department of Medicine III, Dr. Horst Schmidt Klinik, Wiesbaden; ¶Department of Medicine (Cancer Research), West German Cancer Center, University Hospital Essen Germany, Essen; #Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach; and **Asklepios Fachkliniken, München-Gauting, Germany.

Disclosure: Holger Fritsch, Birgit Gaschler-Markefski, Gertraud Hanft, and Gerd Munzert have held leadership positions. Martin Schuler is a consultant or member of advisory board for Boehringer Ingelheim; Martin Reck for Hoffmann-La Roche, Lilly, Merck, Pfizer, and AstraZeneca; Joachim von Pawel for Boehringer Ingelheim; and Martin Sebastian for Boehringer Ingelheim and Lilly. Martin Schuler received honoraria from Boehringer Ingelheim; Martin Reck from Hoffmann-La Roche, Lilly, Merck, Pfizer, and AstraZeneca; and Martin Sebastian from Boehringer Ingelheim, Lilly, and Fresenius Biotech.

Address for correspondence: Martin Schuler, MD, Department of Medicine (Cancer Research), West German Cancer Center, University Hospital, Hufelandstrasse 55, 45122 Essen, Germany. E-mail: martin.schuler@uk-essen.de

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Abstract

Objective: To investigate the efficacy, safety, and pharmacokinetics of two dosing schedules of BI 2536, a novel polo-like kinase-1 inhibitor, in patients with relapsed stage IIIB/IV non-small cell lung cancer.

Methods: Ninety-five patients were randomized to intravenous BI 2536 on day 1 (200 mg) or days 1 to 3 (50 or 60 mg) of a 21-day treatment course. BI 2536 doses were escalated beyond course 2 if well tolerated. The primary objective was response, and the secondary objectives were progression-free survival (PFS) and overall survival (OS), quality of life, safety, and pharmacokinetics. Primary statistical aim was to demonstrate the difference in objective response rate to historical placebo for both treatment groups.

Results: Four patients (4.2%) had a partial response; two were confirmed by independent review. Median PFS was 8.3 weeks (58 days 95% confidence interval [CI]: 48–85) and 7 weeks (49 days 95% CI: 46–70) assessed by investigator and independent review, respectively. Median OS was 28.7 weeks (201 days 95% CI: 180–305). No statistically significant difference was observed between the two treatment schedules regarding clinical benefit, PFS, or OS. Grade 4 neutropenia occurred in 37% of patients; common nonhematologic adverse events were fatigue (31%) and nausea (27%). Two deaths (pulmonary hemorrhage and sepsis) were considered drug related. There was a trend in favor of the days 1 to 3 dosing schedule in quality of life. BI 2536 displayed moderate interpatient variability.

Conclusions: BI 2536 monotherapy has modest efficacy and favorable safety in relapsed non-small cell lung cancer. The findings support the further development of polo-like kinase-1 inhibitors within this indication.

New therapies targeting the cell cycle offer an attractive alternative for the treatment of cancer.1,2 Taxanes and vinca alkaloids are mitotic inhibitors that prevent cellular proliferation by primarily inhibiting the assembly or disrupting the disassembly of microtubules.3 However, their use is compromised as they also effect the cytoskeleton of normal, resting cells, resulting in unwanted toxicities and a low therapeutic index.3

Polo-like kinases (Plks) are a family of highly conserved serine/threonine protein kinases. Plks control the mitotic entry of proliferating cells and the regulation of mitotic progression, specifically the metaphase-anaphase transition and mitotic exit.2 The majority of these functions are attributed to Plk-1, the most extensively characterized mammalian Plk.2,4 Plk-1 initiates entry into mitosis, promotes centrosome separation and maturation, promotes metaphase to anaphase transition and mitotic entry, and allows the onset of cell division.

The Plk-1 is overexpressed in approximately 80% of human tumors, is associated with a poor prognosis,2,4–6 and is upregulated in malignancies with high mitotic activity, including non-small cell lung cancer (NSCLC).2,7 Plk-1 has two highly conserved functional domains, serving as the potential target sites.2 Furthermore, Plk-1 is active during mitosis and does not seem to have a role in nondividing cells.3 Agents designed to inhibit Plk-1 may be viable alternatives to currently available antimitotics. This is supported by preclinical data demonstrating that Plk-1 inhibition prevents the proliferation of cancer cells in vitro.8 Plk-1 knockout experiments also report cell cycle arrest and apoptosis in human cancer cell lines.8

The dihydropteridinone derivative BI 2536 is a novel, potent Plk-1 inhibitor. BI 2536 is highly selective for Plk-1 (IC50 = 0.83 nM) and demonstrates a greater than 10,000-fold selectivity against a large panel of other kinases.9 Preclinical data demonstrate that BI 2536 disrupts spindle assembly causing mitotic arrest (polo-arrest) and inducing apoptosis.9,10 The potential therapeutic effects of Plk-1 inhibition were investigated using cell lines and animal models harboring RAS oncogenic mutations.11 Plk-1 inhibition by BI 2536 resulted in a disruption in mitosis, specifically prometaphase accumulation, and the subsequent death of RAS mutant cells. In agreement with in vitro findings, RAS mutant mouse xenograft models demonstrated significantly attenuated tumor growth after treatment with BI 2536. However, because BI 2536 demonstrated comparable antitumor activity in RAS mutant versus wild-type cell lines,9 patients were not preselected for RAS mutational status for clinical investigation.

Data from the first in-man studies investigating the safety and pharmacokinetics (PKs) of BI 2536 in patients with advanced tumors demonstrated that BI 2536 was well tolerated, had a favorable PK profile, and showed potential antitumor activity.12–14 When BI 2536 was administered as a single intravenous (iv) infusion or a daily infusion for 3 days, the maximum tolerated doses were 200 and 60 mg/d for the single iv infusion and the 3-consecutive-day infusion, respectively.14 The most frequently observed adverse events (AEs) consisted of nausea, anorexia, fatigue, vomiting, and mucositis and were mostly of mild to moderate intensity. The clinical phase I program indicated that single doses of 200 mg BI 2536 may be safely administered in patients with advanced solid tumors.14 BI 2536 also showed encouraging results in the patients with NSCLC when combined with pemetrexed.15

The primary objective of this trial was to assess the efficacy of BI 2536 in patients with stage IIIB/IV NSCLC who relapsed after, or failed, first- or second-line chemotherapy. The secondary objectives included the safety and PKs of two different BI 2536 dosing schedules.

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PATIENTS AND METHODS

Study Design

This was a randomized, phase II, open-label, multicenter study performed between July 2006 and April 2008. Patients were randomly allocated to one of the two treatment groups stratified by center. One group received a single dose of 200 mg BI 2536 on day 1 of each course; the second group received a single dose of 50 mg BI 2536 on days 1, 2, and 3 of each course. This dose was increased to 60 mg after the implementation of a protocol amendment. BI 2536 was administered as an iv infusion for over a 60-minute period. One treatment course comprised 21 days; treatment was continued until tumor progression or the appearance of nontolerable toxicity. In patients who continued BI 2536 therapy beyond course 2, dose escalation was encouraged in case of nonprogression and good tolerability. Dose escalation steps could not exceed 50 mg for the day 1 dosing schedule or 10 mg/day for the 3-day dosing schedule.

Patients who experienced an AE could be continued on therapy at a reduced dose after partial or full recovery. Patients were permitted to have only one dose reduction during the trial.

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Study Population

Male or female patients aged at least 18 years with a life expectancy of at least 3 months and an Eastern Cooperative Oncology Group score of 0–2 were included in the study. Patients were required to have histologically or cytologically confirmed stage IIIB/IV NSCLC and had progressed or failed previous first- or second-line chemotherapy. Patients had to have at least one measurable tumor target lesion according to Response Evaluation Criteria in Solid Tumors.16 Previous chemotherapy, hormonetherapy, immunotherapy, or radiotherapy, or treatment with any other investigational drug was permitted until 4 weeks before the start of study medication. Patients with a history of brain metastases were eligible if they did not require therapy or were asymptomatic. All patients had to have recovered from any toxicities related to previous therapy and had to comply with the study protocol.

Patients who had received more than two previous antitumor therapies or who were considered by the investigator to be eligible for treatment with other second-line chemotherapy, radiotherapy, or immunotherapy were excluded. Patients with hypersensitivity to the trial drug or the excipients, or relevant concomitant comorbidities, were excluded. Patients with a known secondary malignancy requiring therapy, compromised bone marrow function, and impaired renal or liver function were also excluded. Exclusion criteria also covered sexually active patients unwilling to use a medically acceptable method of contraception during the trial and pregnant or breast-feeding women.

The trial was carried out in compliance with the protocol; the ethical principles laid down in the Declaration of Helsinki (1996 Version) in accordance with the International Conference on Harmonisation, Harmonised Tripartite Guideline for good clinical practice, with the European union Clinical Trial Directive and relevant BI standard operating procedures, and in accordance with applicable local regulatory guidelines and requirements. Written informed consent was obtained from each patient before their participation in the study.

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Concomitant Medications

The use of growth factors for the treatment of hematotoxicity was permitted, as were concomitant medications or therapy to provide adequate care. Palliative radiotherapy was permitted if radiotherapy did not affect the target lesions and was not a sign of disease progression.

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Efficacy Assessments

Efficacy was assessed in terms of objective tumor response according to RECIST,16 including clinical deterioration of the cancer disease. Patients were assessed at the end of every other course by the investigator and by an independent reviewer after trial completion. Progression-free survival (PFS) and overall survival (OS) were defined as the time from randomization to progression/death or death.

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Safety Assessments

Incidence and intensity of AEs (CTCAE version 3.0) change in laboratory safety parameters, the occurrence of dose-limiting toxicities, changes in quality of life (QoL) parameters, vital signs, weight, and electrocardiograms were used to assess the safety and tolerability. Dose-limiting toxicities mandating dose reduction was defined as drug-related CTCAE grade ≥3 nonhematological toxicity (excluding untreated nausea, vomiting, or diarrhea) or drug-related CTCAE grade 4 neutropenia for 7 or more days and/or complicated by infection or CTCAE grade 4 thrombocytopenia. QoL was measured by the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 and its lung cancer module by European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-LC13.17 QoL was assessed at screening, at each treatment course, and at the end of treatment. Questionnaires were filled in by patients before the clinical assessment and before receiving any new information regarding their disease status. An improvement of the QoL assessment was defined as a minimum change of 10 points on the standardized global health status QoL score.18 The time to deterioration (a 10-point increase from the baseline score) for cough, dyspnea, and pain was assessed.

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PK Sampling and Data Analysis

The samples were obtained before and after BI 2536 administration and on day 6 of the treatment cycle. BI 2536 concentrations were determined by a validated high performance liquid chromatography and tandem mass spectrometry assay.

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Statistical Analyses

The primary aim of this study was to demonstrate superiority in objective response rate for both BI 2536 treatment groups pooled together compared with putative placebo (historical control, response rate 0.9%; 95% confidence interval [CI]: 0.2–3.0)19 for both treatment groups pooled together. The secondary aim was to estimate the proportion of patients with an objective response and to compare historically with that of other anticancer drugs investigated in the trial indication (historical control, response rate 8.9%; 95% CI: 7–12).19 A one-sided exact binomial test with a 2.5% significance level was used to detect the difference to the historical control. The Simon's ranking and selection approach were used to detect differences in an exploratory manner with regard to both efficacy and safety between the two treatment schedules.20 Randomization was considered as day 1 of the first treatment course.

All patients who received at least one dose of BI 2536 (treated set) were included in the efficacy and safety analyses. With a sample size of 90 patients in total, an exact binomial test with a nominal 0.025 one-sided significance level would demonstrate 80% power to show a difference when compared with placebo, taking the response rate of both treatment groups together. PFS and OS, and time to deterioration of QoL were analyzed by the Kaplan-Meier method and Greenwoods variance estimate for confidence intervals. Maximum percentage change of target lesions' size from baseline were displayed in a Waterfall plot.

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RESULTS

Patient Population

A total of 95 patients were treated in the study. One patient was enrolled later but neither randomized nor treated. Patient demographics and clinical characteristics are presented in Table 1. Patient disposition throughout the study is presented in the Consolidated Standards of Reporting Trials (CONSORT) diagram (Figure 1).

Table 1
Table 1
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Figure 1
Figure 1
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Fourteen patients were dose escalated, 10 in the days 1 to 3 dosing schedule (up to 70 mg) and four in the day 1 dosing schedule (up to 300 mg).

Fifty-four percent of patients treated received two treatment courses; 17% and 15% of the patients had four and six treatment courses, respectively. Seven patients were exposed to more than six treatment courses with two patients exposed to a maximum of 16 and 18 treatment courses (one patient in each dosing schedule).

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Efficacy

Summarized efficacy results are displayed in Table 2. Four of the 95 treated patients had a PR according to the investigator's judgment (response rate 4.2%, 95% CI: 1.2–10.4; p = 0.0017 for putative placebo comparison and p = 0.93 for active historical control comparison) after treatment with BI 2536. Two of these were confirmed by independent review (response rate 2.1%, 95% CI: 0.3–7.4; p = 0.0548 for putative placebo comparison and p = 0.99 for active historical control comparison). The remaining two patients had a PR with regard to the nontarget lesions, whereas no target lesions were identified by the independent reviewer. All four patients had stage IV disease.

Table 2
Table 2
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The independent reviewer also reported three additional patients with a 30% decrease in tumor size of target lesions, which would correspond to a PR. However, these patients were considered progressive by the investigator with regard to the target lesions identified by the investigator. The maximum change in the size of tumor target lesions from baseline as measured by the independent review is shown in Figure 2. No statistically significant difference in PFS was observed between the two treatment schedules. However, data from the independent review indicated a moderate prolongation of PFS for the day 1 dosing schedule (95% CI: 0.98, 3.05, p = 0.06) when clinical progression without documented radiologic progression was not considered in the analysis. The median OS was 33.9 (237 days, 95% CI: 179–370) and 28 weeks (196 days, 95% CI: 176–275) for the day 1 and days 1 to 3 dosing schedules, respectively (Figure 3).

Figure 2
Figure 2
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Figure 3
Figure 3
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Safety and Tolerability

The most frequently reported AEs are presented in Table 3. CTCAE grade 4 AEs were mainly neutropenia. Two patients had CTCAE grade 4 dyspnea, and one patient had CTCAE grade 4 hyperbilirubinemia, bone pain, and metastasis to the central nervous system on the days 1 to 3 schedule, respectively.

Table 3
Table 3
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Forty patients experienced a serious adverse event on treatment. A total of 53 patients died because of disease progression. Two patients died because of an AE that was considered drug related by the investigator (one patient experienced sepsis and the second patient had a pulmonary hemorrhage for which a causal relationship could not be excluded). In addition, 17 patients died because of reasons other than disease progression during the course and/or follow-up of the trial. One patient experienced febrile neutropenia. Four patients had a reduction in platelets to CTCAE grade 3 (all in the day 1 schedule) and one patients to CTCAE grade 4 (day 1–3 schedule). All patients recovered to CTCAE grade ≤1. In total, 37% of patients experienced CTCAE grade 4 neutropenia according to the laboratory values (48% in the day 1; 26% in the days 1–3 dosing schedule). Twelve patients had grade 3 or 4 complications associated with neutropenia, including sepsis or febrile neutropenia (one patient each) and fever or infection associated with low neutrophil count (10 patients).

Sixty-seven patients could be analyzed for the individual scales of the QoL assessment. The median time to deterioration of cough, dyspnea, and pain was 107 (95% CI: 76–171), 83 (95% CI: 58–125), and 74 (95% CI: 43–107) days, respectively, for all patients. Within the first 180 days, a difference was observed between the two dosing schedules for the median time to deterioration of dyspnea with a longer time span of being well in the days 1 to 3 dosing schedule when being treated with 50 mg (176 days, 95% CI: 93–198) when compared with the day 1 dosing schedule with 56 days (95% CI: 32–89). This observation was supported by the fact that approximately 50% of the patients treated with 50 mg BI 2536 reported an improvement in dyspnea compared with 33% of patients treated in the day 1 dosing schedule. In contrast, 56% of patients had a worsening of dyspnea in this group. However, patients in the days 1 to 3 dosing schedule reported dyspnea as an AE more frequently than patients in the day 1 dosing schedule. Although the majority of the QoL parameters were comparable for the two dosing schedules, there was a trend in favor of the days 1 to 3 dosing schedule for the functional scales “emotional functioning” and “role functioning,” with more patients reporting a deterioration on the day 1 dosing schedule (Table 4).

Table 4
Table 4
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Plasma Concentration—Time Data

The plasma concentration of BI 2536 increased during the infusion period. After the end of infusion, BI 2536 showed a fast disposition phase. The plasma concentrations of BI 2536 at 120 hours after the 200 mg dose and 72 hours after the 50 and 60 mg dose were approximately 2% of those found directly before the end of infusion.

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DISCUSSION

This open label, randomized, phase II clinical trial investigated the efficacy, safety, and PKs of two doses of BI 2536 in patients with stage IIIB/IV NSCLC. BI 2536 demonstrated modest antitumor activity with an investigator-assessed PR in four of 95 treated patients (4.2%). No significant differences in patient outcomes between the two treatment schedules were observed regarding clinical benefit (acceptable tolerability and at least stable disease), PFS and OS. Despite the fact that the trial was not powered to show significant differences between the treatment arms, there was a trend in favor of the day 1 dosing schedule for median OS and when PFS was analyzed by independent review. Despite the objective response rate being low, the capability of BI 2536 to achieve response rates with low treatment-induced mortality in several patients suggests clinical activity of Plk-1 inhibitors in relapsed NSCLC. Most of the AEs transiently affected the hematopoietic system without causing relevant clinical problems to the majority of patients. Clinical studies with other available antimitotic therapies targeting microtubules report neurologic and hematologic toxicities as the principle AEs.21–25 BI 2536 was generally well tolerated without cumulative toxicity and neurotoxicity, confirming the favorable safety profile obtained in the phase I program. In both this trial and another trial,15 prolonged administration of BI 2536 was feasible.

Three pivotal clinical trials have demonstrated the effectiveness of docetaxel, a taxane, compared with other chemotherapy-based regimens or best supportive care for the treatment of NSCLC.24–26 Efficacy data from our trial indicate that Plk inhibitors such as BI 2536 seem to have modest clinical efficacy in the treatment of NSCLC.

Demonstration of target inhibition in tumor cells is a key priority in the development of a compound with a novel target such as Plk-1 inhibition.27 Plk-1 inhibition resulting in the characteristic “polo arrest” phenotype has been demonstrated in the bone marrow specimens from patients with acute myeloid leukemia, where BI 2536 was administered with the same schedule as in this trial.28 To date, no clinical marker predicting response to Plk-1 inhibition or prolonged disease stabilization has been identified. Biomarker studies could support the optimization of Plk-1 administration schedules and identify the predictive markers.27 Of note, in our study, because of the low number of patients with an objective response, no clinical predictive marker for outcome of treatment with BI 2536 could be identified. However, translational studies investigating the predictors of clinical benefit are ongoing. The potential to improve efficacy by combining a well-tolerated Plk-1 inhibitor with other antitumor agents, including chemotherapy or targeted agents, is another key area of interest.

As a part of the Plk-1 inhibitor development program, it is important to build on these data and to continue to optimize Plk-1 inhibitors. Few Plk inhibitors are currently under investigation for the treatment of various cancer types; however, BI 2536 is the first selective member of the Plk-1 inhibitor class that entered into clinical trials. To further develop this class, BI 6727, a second-generation dihydropteridinone derivative, has an improved PK profile with an increased tissue penetration and a correspondingly prolonged terminal half-life, suggesting an enhanced impact on cancer cells. This compound is currently undergoing phase II investigation in NSCLC. Because of the improved PK profile and promising phase I data, BI 6727 will preferentially be used in future trials.

In summary, these data demonstrate modest efficacy and acceptable safety of BI 2536 monotherapy in relapsed NSCLC. The findings from this study support further development of the Plk-1 inhibitor class for the treatment of NSCLC and other cancer types. Although mechanisms of resistance to BI 2536 and predictors of clinical benefit have not been identified, second-generation Plk-1 inhibitors may be the next step toward developing novel treatment approaches for advanced NSCLC.

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ACKNOWLEDGMENTS

Supported by Boehringer Ingelheim.

The authors thank Ogilvy Healthworld for the editorial assistance and Dr. Martina Wein, Department of Drug Metabolism and Pharmacokinetics, for bioanalytical support.

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REFERENCES

1. Swanton C. Cell-cycle targeted therapies. Lancet Oncol 2004;5:27–36.

2. Yap TA, Molife LR, Blagden SP, et al. Targeting cell cycle kinases and kinesins in anticancer drug development. Expert Opin Drug Discov 2007;2:539–560.

3. Jackson JR, Patrick DR, Dar MM, et al. Targeted anti-mitotic therapies: can we improve on tubulin agents? Nat Rev Cancer 2007;7:107–117.

4. Eckerdt F, Yuan J, Strebhardt K. Polo-like kinases and oncogenesis. Oncogene 2005;24:267–276.

5. Strebhardt K, Ullrich A. Targeting polo-like kinase 1 for cancer therapy. Nat Rev Cancer 2006;6:321–330.

6. Holtrich U, Wolf G, Brauninger A, et al. Induction and down-regulation of PLK, a human serine/threonine kinase expressed in proliferating cells and tumors. Proc Natl Acad Sci USA 1994;91:1736–1740.

7. Wolf G, Elez R, Doermer A, et al. Prognostic significance of polo-like kinase (PLK) expression in non-small cell lung cancer. Oncogene 1997;14:543–549.

8. Liu X, Erikson RL. Polo-like kinase (Plk)1 depletion induces apoptosis in cancer cells. Proc Natl Acad Sci USA 2003;100:5789–5794.

9. Steegmaier M, Hoffmann M, Baum A, et al. BI 2536, a potent and selective inhibitor of polo-like kinase 1, inhibits tumor growth in vivo. Curr Biol 2007;17:316–322.

10. Lenart P, Petronczki M, Steegmaier M, et al. The small-molecule inhibitor BI 2536 reveals novel insights into mitotic roles of polo-like kinase 1. Curr Biol 2007;17:304–315.

11. Luo J, Emanuele MJ, Li D, et al. A genome-wide RNAi screen identifies multiple synthetic lethal interactions with the Ras oncogene. Cell 2009;137:835–848.

12. Mross K, Frost A, Steinbild S, et al. Phase I dose escalation and pharmacokinetic study of BI 2536, a novel Polo-like kinase 1 inhibitor, in patients with advanced solid tumors. J Clin Oncol 2008;26:5511–5517.

13. Hofheinz R, Hochhaus A, Al-Batran S, et al. A phase I repeated dose escalation study of the Polo-like kinase 1 inhibitor BI 2536 in patients with advanced solid tumour. J Clin Oncol 2006;24:2038.

14. Munzert G, Steinbild S, Frost A, et al. A phase I study of two administration schedules of the Polo-like kinase 1 inhibitor BI 2536 in patients with advanced solid tumors. J Clin Oncol 2006;24:3069.

15. Ellis PM, Chu QS, Leighl NB, et al. A phase I dose escalation trial of BI 2536, a novel Plk1 inhibitor, with standard dose pemetrexed in previously treated advanced or metastatic non-small cell lung cancer (NSCLC) [abstract]. J Clin Oncol 2008;26:8115.

16. Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 2000;92:205–216.

17. Aaronson NK, Ahmedzai S, Bergman B, et al. The European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst 1993;85:365–376.

18. Osoba D, Rodrigues G, Myles J, et al. Interpreting the significance of changes in health-related quality-of-life scores. J Clin Oncol 1998;16:139–144.

19. Shepherd FA, Rodrigues Pereira J, Ciuleanu T, et al. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 2005;353:123–132.

20. Simon R, Wittes RE, Ellenberg SS. Randomized phase II clinical trials. Cancer Treat Rep 1985;69:1375–1381.

21. Trudeau ME. Docetaxel: a review of its pharmacology and clinical activity. Can J Oncol 1996;6:443–457.

22. Zhou J, Giannakakou P. Targeting microtubules for cancer chemotherapy. Curr Med Chem Anticancer Agents 2005;5:65–71.

23. Schmidt M, Bastians H. Mitotic drug targets and the development of novel anti-mitotic anticancer drugs. Drug Resist Updat 2007;10:162–181.

24. Shepherd FA, Dancey J, Ramlau R, et al. Prospective randomized trial of docetaxel versus best supportive care in patients with non-small-cell lung cancer previously treated with platinum-based chemotherapy. J Clin Oncol 2000;18:2095–2103.

25. Fossella FV, DeVore R, Kerr RN, et al. Randomized phase III trial of docetaxel versus vinorelbine or ifosfamide in patients with advanced non-small-cell lung cancer previously treated with platinum-containing chemotherapy regimens. The TAX 320 Non-Small Cell Lung Cancer Study Group. J Clin Oncol 2000;18:2354–2362.

26. Hanna N, Shepherd FA, Fossella FV, et al. Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy. J Clin Oncol 2004;22:1589–1597.

27. Olmos D, Swanton C, de Bono J. Targeting polo-like kinase: learning too little too late? J Clin Oncol 2008;26:5497–5499.

28. Lee K-H, Schlenk RF, Bug G, et al. Polo-like kinase-1 (Plk-1) inhibitor BI 2536 induces mitotic arrest and apoptosis in vivo: first demonstration of target inhibition in the bone marrow of AML patients. Blood (ASH Annual Meeting Abstracts) 2008;112:2641.

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Keywords:

Plk-1 kinase inhibition; BI 2536; Stage IIIB/IV NSCLC; Phase II

© 2010International Association for the Study of Lung Cancer

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