Phase I Dose Escalation and Pharmacokinetic Study of BI 2536, a Novel Polo-Like Kinase 1 Inhibitor, in Patients With Advanced Solid Tumors

Mross, Klaus; Frost, Annette; Steinbild, Simone; Hedbom, Susanne; Rentschler, Jochen; Kaiser, Rolf; Rouyrre, Nicolas; Trommeshauser, Dirk; Hoesl, Cornelia E.; Munzert, Gerd

doi:10.1200/jco.2008.16.1547

Cited by 147 publications

(149 citation statements)

References 20 publications

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“…However, delayed toxicity, manifest as a drastic decrease in peripheral WBCs, was evident within 24-36 h after free drug administration. This type of toxicity was identical to that observed in human clinical trials (53)(54)(55). Although toxic to bone marrow, the free BI-2536 was able to induce a significant antitumor response, slowing tumor growth by ∼30% after two doses at its maximum tolerated dose (MTD) (Fig.…”

Section: Chemically Modified β-Cyclodextrins Can Encapsulate Small Hysupporting

confidence: 75%

“…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%

See 1 more Smart Citation

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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Section: Chemically Modified β-Cyclodextrins Can Encapsulate Small Hysupporting

confidence: 75%

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

View full text Add to dashboard Cite

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“…Whether this was because of inadequate concentrations of Nutlin-3 in vivo for prolonged periods is not known. On the other hand, the major toxicity of BI-2536 in Phase I trials has been hematopoietic, with dangerous levels of neutropenia observed after treatment with this agent in the majority of patients (51). To determine whether Nutlin-3 could rescue this toxicity, we administered the combination of oral Nutlin-3 (200 mg/kg) and BI-2536 (100 mg/kg) to BALB/c mice.…”

Section: Transcriptional Profile Of Cells With and Without Wt Tp53mentioning

confidence: 99%

A panel of isogenic human cancer cells suggests a therapeutic approach for cancers with inactivated p53

Sur

Pagliarini

Bunz

et al. 2009

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

270

289

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Through targeted homologous recombination, we developed a panel of matched colorectal cancer cell lines that differ only with respect to their endogenous TP53 status. We then used these lines to define the genes whose expression was altered after DNA damage induced by ionizing radiation. Transcriptome analyses revealed a consistent upregulation of polo-like kinase 1 (PLK1) as well as other genes controlling the G 2/M transition in the cells whose TP53 genes were inactivated compared with those with WT TP53 genes. This led to the hypothesis that the viability of stressed cells without WT TP53 depended on PLK1. This hypothesis was validated by demonstrating that stressed cancer cells without WT TP53 alleles were highly sensitive to PLK1 inhibitors, both in vivo and in vitro.

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“…BI 2536, 46 BI 6727 47 and GSK461364 48 showed antitumor activity and stabilized disease in a subset of patients with advanced solid tumors, with manageable and reversible toxicity. Based on our results, it is plausible that PLK1-targeting drugs may also have therapeutic potential in childhood ALL.…”

Section: Discussionmentioning

confidence: 99%

Inhibiting Polo-like kinase 1 causes growth reduction and apoptosis in pediatric acute lymphoblastic leukemia cells

et al. 2013

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This study investigated Polo-like kinase 1, a mitotic regulator often over-expressed in solid tumors and adult hematopoietic malignancies, as a potential new target in the treatment of pediatric acute lymphoblastic leukemia. Polo-like kinase 1 protein and Thr210 phosphorylation levels were higher in pediatric acute lymphoblastic leukemia (n=172) than in normal bone marrow mononuclear cells (n=10) (P<0.0001). High Polo-like kinase 1 protein phosphorylation, but not expression, was associated with a lower probability of event-free survival (P=0.042) and was a borderline significant prognostic factor (P=0.065) in a multivariate analysis including age and initial white blood cell count. Polo-like kinase 1 was necessary for leukemic cell survival, since short hairpin-mediated Polo-like kinase 1 knockdown in acute lymphoblastic leukemia cell lines inhibited cell proliferation by G2/M cell cycle arrest and induced apoptosis through caspase-3 and poly (ADP-ribose) polymerase cleavage. Primary patient cells with a high Polo-like kinase 1 protein expression were sensitive to the Polo-like kinase 1-specific inhibitor NMS-P937 in vitro, whereas cells with a low expression and normal bone marrow cells were resistant. This sensitivity was likely not caused by Polo-like kinase 1 mutations, since only one new mutation (Ser335Arg) was found by 454-sequencing of 38 pediatric acute lymphoblastic leukemia cases. This mutation did not affect Polo-like kinase 1 expression or NMS-P937 sensitivity. Together, these results indicate a pivotal role for Polo-like kinase 1 in pediatric acute lymphoblastic leukemia and show potential for Polo-like kinase 1-inhibiting drugs as an addition to current treatment strategies for cases expressing high Polo-like kinase 1 levels. ABSTRACTinhibitor highly selective for PLK1 and the first orally administered selective PLK1 inhibitor entering phase I clinical trials 25 (clinicaltrials.gov identifier: NCT01014429). This study shows the potential of PLK1-targeting therapeutics in the treatment of childhood ALL, and indicates their value for further clinical evaluation. Methods Cell linesCell lines (DSMZ, Braunschweig, Germany) were cultured in RPMI+Glutamax with pen-strep, fungizone (Life Technologies, Bleiswijk, The Netherlands) and 10% or 20% fetal calf serum (Integro, Zaandam, The Netherlands), at 37ºC and 5% CO 2 .

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Phase I Dose Escalation and Pharmacokinetic Study of BI 2536, a Novel Polo-Like Kinase 1 Inhibitor, in Patients With Advanced Solid Tumors

Abstract: The MTD of BI 2536 when administered as a single-dose, 1-hour infusion was 200 mg; BI 2536 was well tolerated and showed a favorable pharmacokinetic profile. Antitumor activity of BI 2536 was observed.

Cited by 147 publications

References 20 publications

Remote loading of preencapsulated drugs into stealth liposomes

Remote loading of preencapsulated drugs into stealth liposomes

A panel of isogenic human cancer cells suggests a therapeutic approach for cancers with inactivated p53

Inhibiting Polo-like kinase 1 causes growth reduction and apoptosis in pediatric acute lymphoblastic leukemia cells

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