An Open-Label, Phase I Study of the Polo-like Kinase-1 Inhibitor, BI 2536, in Patients with Advanced Solid Tumors

Hofheinz, Ralf–Dieter; Al‐Batran, Salah‐Eddin; Hochhaus, Andreas; Jäger, Elke; Reichardt, Volker L.; Fritsch, Holger; Trommeshauser, Dirk; Munzert, Gerd

doi:10.1158/1078-0432.ccr-10-0318

Cited by 83 publications

(69 citation statements)

References 16 publications

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“…In parallel with the present study, BI 2536 was also investigated in another phase i repeated dose-escalation study in patients with advanced solid tumours 20 .…”

Section: Discussionmentioning

confidence: 92%

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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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“…In parallel with the present study, BI 2536 was also investigated in another phase i repeated dose-escalation study in patients with advanced solid tumours 20 .…”

Section: Discussionmentioning

confidence: 92%

“…In that study, patients received intravenous infusions of BI 2536 on days 1 and 8 of a 3-week treatment course 20 . The mtd for the latter dosing schedule was defined as 200 mg (100 mg on day 1 and 100 mg on day 8).…”

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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“…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.

122

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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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“…Volasertib has shown in vivo efficacy in multiple xenograft models, including AML. A predecessor compound, BI 2536, 15,16 was previously evaluated in older patients with relapsed/refractory AML and provided a first proof-of-principle of the potential therapeutic value of targeting Plk in patients with AML. 17 Clinical development of BI 2536 was discontinued in favor of volasertib, which has an improved pharmacokinetic profile.…”

Section: Introductionmentioning

confidence: 99%

Randomized, phase 2 trial of low-dose cytarabine with or without volasertib in AML patients not suitable for induction therapy

Döhner

Lübbert

Fiedler

et al. 2014

Blood

Self Cite

208

163

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Key Points• Volasertib plus low-dose cytarabine increased the response rate and improved survival in AML patients ineligible for intensive treatment.• Volasertib plus low-dose cytarabine resulted in responses across all AML genetic subgroups and had a clinically manageable safety profile.Treatment outcomes for older patients with acute myeloid leukemia (AML) have remained dismal. This randomized, phase 2 trial in AML patients not considered suitable for intensive induction therapy compared low-dose cytarabine (LDAC) with or without volasertib, a highly potent and selective inhibitor of polo-like kinases. Eighty-seven patients (median age 75 years) received LDAC 20 mg twice daily subcutaneously days 1-10 or LDAC 1 volasertib 350 mg IV days 1 1 15 every 4 weeks. Response rate (complete remission and complete remission with incomplete blood count recovery) was higher for LDAC 1 volasertib vs LDAC (31.0% vs 13.3%; odds ratio, 2.91; P 5 .052). Responses in the LDAC 1 volasertib arm were observed across all genetic groups, including 5 of 14 patients with adverse cytogenetics. Median event-free survival was significantly prolonged by LDAC 1 volasertib compared with LDAC (5.6 vs 2.3 months; hazard ratio, 0.57; 95% confidence interval, 0.35-0.92; P 5 .021); median overall survival was 8.0 vs 5.2 months, respectively (hazard ratio, 0.63; 95% confidence interval, 0.40-1.00; P 5 .047). LDAC 1 volasertib led to an increased frequency of adverse events that was most pronounced for neutropenic fever/infections and gastrointestinal events; there was no increase in the death rate at days 60 1 90. This study was

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An Open-Label, Phase I Study of the Polo-like Kinase-1 Inhibitor, BI 2536, in Patients with Advanced Solid Tumors

Cited by 83 publications

References 16 publications

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

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

Randomized, phase 2 trial of low-dose cytarabine with or without volasertib in AML patients not suitable for induction therapy

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