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; Reck, Martin; Waller, Christiane; Kortsik, C.; Frickhofen, Norbert; Schüler, Martin; Fritsch, Holger; Gaschler‐Markefski, Birgit; Hanft, Gertraud; Munzert, Gerd; Pawel, Joachim von

doi:10.1097/jto.0b013e3181d95dd4

Cited by 98 publications

(92 citation statements)

References 26 publications

(35 reference statements)

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“…In phase I, dose-escalation and pharmacokinetic studies of BI 2536 in patients with advanced solid tumors, the maximum tolerated dose was 200 mg, which would produce an estimated tissue concentration of approximately 10 mM (consistent with the measured plasma concentrations of 1À10 mM) [17]. BI 2536 is currently in phase II/III clinical studies, although this is not the only Plk1 inhibitor under development.…”

Section: Discussionmentioning

confidence: 77%

The polo-like kinase inhibitor BI 2536 exhibits potent activity against malignant plasma cells and represents a novel therapy in multiple myeloma

Stewart

Kishikova

Powell

et al. 2011

Experimental Hematology

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Objective. Polo-like kinase 1 (Plk1) is a regulator of the cell cycle that has been implicated in the pathology of many cancers. We have investigated whether this kinase plays a role in multiple myeloma (MM) using the Plk1 inhibitor BI 2536. Materials and Methods. We have used six MM cell lines and six patient-derived samples to determine the effects of the Plk1 inhibitor, BI 2536, on cell viability, apoptosis, and cytokinesis. We have also examined the effect of the microenvironment on these parameters and the effects of BI 2536 in combination with other antimyeloma agents. Results. We show that MM cell lines and patient samples express PLK1 and that cell death by apoptosis occurs when Plk1 is inhibited. Cells treated with BI 2536 accumulate in the G 2 /M phase of the cell cycle causing endoduplication. The effects of BI 2536 are not abrogated when cells are cultured on extracellular matrix components, in the presence of interleukin-6, or with bone marrow stromal cells. Conclusions. Plk1 inhibition leads to cell death in MM cell lines and patient myeloma samples. Our data suggest that inhibition of Plk1 may have potential use as a therapeutic strategy in multiple myeloma. Ó

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Section: Discussionmentioning

confidence: 77%

The polo-like kinase inhibitor BI 2536 exhibits potent activity against malignant plasma cells and represents a novel therapy in multiple myeloma

Stewart

Kishikova

Powell

et al. 2011

Experimental Hematology

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“…Although a number of other compounds that target the Plk pathway are under investigation [8][9][10] , BI 2536 is the first selective member of the Plk1 inhibitor class to have begun clinical trials, wherein it has been evaluated in the treatment of patients with solid tumours, including metastatic or advanced pancreatic cancer 21 , prostate cancer 22 , and nsclc [as monotherapy 23 and in combination with pemetrexed 24 ]. Although antitumour efficacy has been noted in individual patients in these clinical trials, overall antitumour activity-in terms of response rate, duration of response, clinical benefit, and progressionfree survival-was disappointing.…”

Section: Discussionmentioning

confidence: 99%

Phase I Study of the Plk1 Inhibitor BI 2536 Administered Intravenously on Three Consecutive Days in Advanced Solid Tumours

Frost¹,

Mross²,

Steinbild³

et al. 2012

Current Oncology

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Background: This open-label phase i study with an accelerated titration design was performed to determine the maximum tolerated dose of BI 2536, a potent, highly selective small-molecule polo-like kinase 1 (Plk1) inhibitor. Methods: Patients with advanced solid tumours received a single 60-minute intravenous infusion of BI 2536 (50–70 mg) on days 1–3 of each 21-day treatment course. Recipients without disease progression or untenable toxicity could receive additional treatment courses. The maximum tolerated dose was determined based on dose-limiting toxicities. Other assessments included safety, pharmacokinetic profile, and antitumour activity according to the Response Evaluation Criteria in Solid Tumors. Results: The study enrolled 21 patients. The maximum tolerated dose for BI 2536 was determined to be 60 mg for the study schedule. Dose-limiting toxicities included hematologic events, hypertension, elevated liver enzymes, and fatigue. The most frequently reported drug-related adverse events were mild-to-moderate fatigue, leukopenia, constipation, nausea, mucosal inflammation, anorexia, and alopecia. The pharmacokinetics of BI 2536 were linear within the dose range tested. Plasma concentration profiles exhibited multi-compartmental pharmacokinetic behaviour, with a terminal elimination half-life of 20–30 hours. Conclusions: In the present study, BI 2536 showed an acceptable safety profile warranting further investigation of Plk1 inhibitors in this patient population.

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“…It has been shown that BI-2536 has potent tumoricidal activity against cancer cells, particularly those harboring mutations in TP53 (44-47). BI-2536 was the subject of several clinical trials in patients with cancers of the lung, breast, ovaries, and uterus (48)(49)(50)(51)(52)(53). Although it showed evidence of efficacy in cancer patients, its development was abandoned after phase II trials revealed unacceptable toxicity (grade 4 neutropenia) at subtherapeutic doses.…”

Section: Chemically Modified β-Cyclodextrins Can Encapsulate Small Hymentioning

confidence: 99%

Remote loading of preencapsulated drugs into stealth liposomes

Sur

Fries

Kinzler

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

124

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Loading drugs into carriers such as liposomes can increase the therapeutic ratio by reducing drug concentrations in normal tissues and raising their concentrations in tumors. Although this strategy has proven advantageous in certain circumstances, many drugs are highly hydrophobic and nonionizable and cannot be loaded into liposomes through conventional means. We hypothesized that such drugs could be actively loaded into liposomes by encapsulating them into specially designed cyclodextrins. To test this hypothesis, two hydrophobic drugs that had failed phase II clinical trials because of excess toxicity at deliverable doses were evaluated. In both cases, the drugs could be remotely loaded into liposomes after their encapsulation (preloading) into cyclodextrins and administered to mice at higher doses and with greater efficacy than possible with the free drugs.T here is currently wide interest in the development of nanoparticles for drug delivery (1-7). This area of research is particularly relevant to cancer drugs, wherein the therapeutic ratio (dose required for effectiveness to dose causing toxicity) is often low. Nanoparticles carrying drugs can increase this therapeutic ratio over that achieved with the free drug through several mechanisms. In particular, drugs delivered by nanoparticles are thought to selectively enhance the concentration of the drugs in tumors as a result of the enhanced permeability and retention (EPR) effect (8-18). The enhanced permeability results from a leaky tumor vascular system, whereas the enhanced retention results from the disorganized lymphatic system that is characteristic of malignant tumors.Much current work in this field is devoted to designing novel materials for nanoparticle generation. This new generation of nanoparticles can carry drugs-particularly those that are insoluble in aqueous medium-that are difficult to incorporate into conventional nanoparticles such as liposomes. However, the older generation of nanoparticles has a major practical advantage in that they have been extensively tested in humans and approved by regulatory agencies such as the Food and Drug Administration in the United States and the European Medicines Agency in Europe. Unfortunately, many drugs cannot be easily or effectively loaded into liposomes, thereby compromising their general use.In general, liposomal drug loading is achieved by either passive or active methods (9,(19)(20)(21)(22). Passive loading involves dissolution of dried lipid films in aqueous solutions containing the drug of interest. This approach can only be used for water-soluble drugs, and the efficiency of loading is often low. In contrast, active loading can be extremely efficient, resulting in high intraliposomal concentrations and minimal wastage of precious chemotherapeutic agents (9,23,24). In active loading, drug internalization into preformed liposomes is typically driven by a transmembrane pH gradient. The pH outside the liposome allows some of the drug to exist in an unionized form, able to migrate across the lipid bi...

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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

Abstract: 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.

Cited by 98 publications

References 26 publications

The polo-like kinase inhibitor BI 2536 exhibits potent activity against malignant plasma cells and represents a novel therapy in multiple myeloma

The polo-like kinase inhibitor BI 2536 exhibits potent activity against malignant plasma cells and represents a novel therapy in multiple myeloma

Phase I Study of the Plk1 Inhibitor BI 2536 Administered Intravenously on Three Consecutive Days in Advanced Solid Tumours

Remote loading of preencapsulated drugs into stealth liposomes

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