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Polo-like kinase 1 (PLK1) regulates mitotic checkpoints and cell division. PLK1 overexpression is reported in numerous cancers, including acute myeloid leukemia (AML), and is associated with poor prognosis. Volasertib is a selective, potent cell-cycle kinase inhibitor that targets PLK to induce mitotic arrest and apoptosis. This phase 1 trial investigated the maximum tolerated dose (MTD), safety, pharmacokinetics, and anti-leukemic activity of volasertib in combination with decitabine in AML patients aged ≥ 65 years. Thirteen patients were treated with escalating volasertib doses (3 + 3 design; 300 mg, 350 mg, and 400 mg) plus standard-dose decitabine. Dose-limiting toxicity was reported in one patient in cycle 1; the MTD of volasertib in combination with decitabine was determined as 400 mg. The most common treatment-emergent adverse events were febrile neutropenia, pneumonia, and decreased appetite. Objective response rate was 23%. The combination was well tolerated, and the adverse event profile was in line with previous findings.

Introduction: Targeting the cell cycle machinery represents a rational therapeutic approach in myelodysplastic syndromes (MDS) and secondary acute myeloid leukemia (sAML). Despite substantial response rates, clinical use of the PLK inhibitor volasertib has been hampered by elevated side effects such as neutropenia and infections., Objectives: The primary objective was to analyse whether a reduced dose of volasertib was able to limit toxic effects on the healthy haematopoiesis while retaining its therapeutic effect., Methods: Bone marrow mononuclear cells (BMMNCs) of patients with MDS/sAML (n = 73) and healthy controls (n = 28) were treated with volasertib (1 μM to 1 nM) or vehicle control. Short-term viability analysis was performed by flow cytometry after 72 hours. For long-term viability analysis, colony-forming capacity was assessed after 14 days. Protein expression of RIPK3 and MCL-1 was quantified via flow cytometry., Results: Reduced dose levels of volasertib retained high cell death-inducing efficacy in primary human stem and progenitor cells of MDS/sAML patients without affecting healthy haematopoiesis in vitro. Interestingly, volasertib reduced colony-forming capacity and cell survival independent of clinical stage or mutational status., Conclusions: Volasertib offers a promising therapeutic approach in patients with adverse prognostic profile. RIPK3 and MCL-1 might be potential biomarkers for sensitivity to volasertib treatment., (© 2019 The Authors. European Journal of Haematology published by John Wiley & Sons Ltd.)

Background: Volasertib induces mitotic arrest and apoptosis by targeting Polo-like kinases. In this phase I dose-escalation study, the maximum tolerated dose (MTD), pharmacokinetics (PK), and preliminary efficacy of volasertib were determined in pediatric patients., Methods: Patients aged 2 to <18 years with relapsed/refractory acute leukemia/advanced solid tumors (ST) without available effective treatments were enrolled-cohort C1 (aged 2 to <12 years); cohort C2 (aged 12 to <18 years). The patients received volasertib intravenously (starting dose: 200 mg/m 2 body surface area on day 1, every 14 days). The primary endpoint was the pediatric MTD for further development., Results: Twenty-two patients received treatment (C1: leukemia, n = 4; ST, n = 8; C2: leukemia, n = 3; ST, n = 7). No dose-limiting toxicities (DLTs) occurred up to 300 mg/m 2 volasertib in C1; two patients in C2, at 250 mg/m 2 volasertib, had DLTs in cycle 1, one of which led to death; therefore, the MTD of volasertib in C2 was 200 mg/m 2 . The most common grade 3/4 adverse events (all patients) were febrile neutropenia, thrombocytopenia, and neutropenia (41% each). Stable disease (SD) was the best objective response (leukemia, n = 5; ST, n = 2); the duration of SD was short in all patients, except in one with an ST. PK profiles were generally comparable across dose groups and were consistent with those in adults., Conclusion: The pediatric MTD/dose for further development was identified. There were no unexpected safety or PK findings; limited antitumor/antileukemic activity was demonstrated., (© 2019 The Authors Pediatric Blood & Cancer Published by Wiley Periodicals, Inc.)

Vesatolimod is an oral agonist of toll-like receptor 7 designed to minimize systemic exposure and side effects. We assessed the safety and efficacy of vesatolimod in viremic chronic hepatitis B (CHB) patients not currently on oral antiviral treatment (OAV) in a phase 2, multicentre, double-blind, randomized, placebo-controlled study. A total of 192 patients stratified by HBeAg status and alanine aminotransferase level were randomized 2:2:2:1 to receive oral vesatolimod (1-, 2- or 4-mg) or placebo once weekly for 12 weeks; tenofovir disoproxil fumarate (300-mg daily) was administered daily for 48 weeks. Efficacy was assessed by quantitative serum HBsAg decline at Week 24 from baseline. In addition to safety assessments, changes in whole-blood interferon-stimulated gene (ISG) transcripts and serum cytokines were explored. Most patients were male (64.1%) and HBeAg-negative (60.9%) at baseline. Among vesatolimod-treated patients, most (60.4%-69.1%) experienced ≥1 treatment-emergent adverse event; the majority were mild or moderate in severity. No clinically meaningful differences in HBsAg changes from baseline were observed between treatment groups. No patients experienced HBsAg loss, while 3 patients experienced HBeAg loss and hepatitis B e-antibody seroconversion at week 48. HBV DNA suppression rates were similar across all treatment arms at Week 24. ISG15 induction was dose-dependent and did not correlate with HBsAg changes. A small proportion of patients exhibited dose-dependent interferon-α induction that correlated with grade of influenza-like adverse events. Overall, vesatolimod is safe and well tolerated in CHB patients. Although consistent dose-dependent pharmacodynamic induction of ISGs was demonstrated, it did not result in clinically significant HBsAg decline., (© 2018 John Wiley & Sons Ltd.)

Volasertib is a selective cell cycle kinase inhibitor that induces mitotic arrest and apoptosis by targeting Polo-like kinase (Plk). A potential for prolonged QT intervals was indicated with volasertib in preclinical studies and preliminary clinical data. As a result, electrocardiograms (ECGs) have been collected in all volasertib clinical trials to monitor potential cardiac effects. This article describes strategic and statistical methods prospectively planned to perform an integrated analysis of ECG data from available trials to evaluate volasertib's effect on cardiac repolarization, as reflected by changes in the duration of QT interval and other ECG-related endpoints. Methods to effectively cope with heterogeneity between trials (ie, differences in study designs) are discussed. These strategies may be useful for other investigational drugs for which QT risk assessment is required, but a thorough QT/QTc trial is not feasible, resulting in the need for an alternative approach. Volasertib therapy relevantly prolonged adjusted mean QTcF change from administration baseline following the first and subsequent infusions. The integrated analysis revealed that the volasertib effects on the mean QTc changes from baseline were transient and had resolved at 24 hours after start of the first infusion. There was no evidence for a long-term impact on the QTcF interval following multiple infusions with volasertib.

Antiretroviral therapy (ART) can halt HIV-1 replication but fails to target the long-lived latent viral reservoir. Several pharmacological compounds have been evaluated for their ability to reverse HIV-1 latency, but none has demonstrably reduced the latent HIV-1 reservoir or affected viral rebound after the interruption of ART. We evaluated orally administered selective Toll-like receptor 7 (TLR7) agonists GS-986 and GS-9620 for their ability to induce transient viremia in rhesus macaques infected with simian immunodeficiency virus (SIV) and treated with suppressive ART. In an initial dose-escalation study, and a subsequent dose-optimization study, we found that TLR7 agonists activated multiple innate and adaptive immune cell populations in addition to inducing expression of SIV RNA. We also observed TLR7 agonist-induced reductions in SIV DNA and measured inducible virus from treated animals in ex vivo cell cultures. In a second study, after stopping ART, two of nine treated animals remained aviremic for more than 2 years, even after in vivo CD8 + T cell depletion. Moreover, adoptive transfer of cells from aviremic animals could not induce de novo infection in naïve recipient macaques. These findings suggest that TLR7 agonists may facilitate reduction of the viral reservoir in a subset of SIV-infected rhesus macaques., (Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Background & Aims: Vesatolimod (GS-9620) is an oral agonist of toll-like receptor 7, an activator of innate and adaptive immune responses. Herein the safety and efficacy of vesatolimod is assessed after once-weekly treatment in patients with chronic hepatitis B (CHB) infection suppressed on oral antiviral treatment., Methods: In a phase II, double-blind, randomized, placebo (PBO)-controlled study, 162 patients stratified by hepatitis B surface antigen (HBsAg) levels and serum hepatitis B e antigen (HBeAg) status were randomized 1:3:3:3 to once-weekly oral PBO or vesatolimod (1-, 2-, or 4-mg doses) for 4, 8 or 12 weeks per cohort. Efficacy was assessed by change in baseline HBsAg (log 10 IU/ml) at the primary endpoint (Week 24). Safety assessments included adverse events (AE) and laboratory abnormality monitoring. Pharmacodynamic assessments included peripheral cytokine level quantification and interferon-stimulated gene (ISG) mRNA expression evaluation., Results: The majority of patients were male (76%) and HBeAg-negative (79%) at baseline. Most (41-80%) experienced ≥1 AE during the study with the majority of AEs mild or moderate in severity. No significant declines in HBsAg were observed at the primary (Week 24) or secondary endpoints (Weeks 4, 8, 12, and 48). ISG15 induction was dose-dependent and consistent after repeat dosing, returning closer to baseline by one week after treatment at all dose levels; no patient demonstrated significant serum interferon alpha (IFNα) expression at any timepoint evaluated. Multivariate analyses showed that ≥2-fold ISG15 induction is associated with 2- or 4-mg vesatolimod dose and female sex., Conclusions: Vesatolimod was safe and well-tolerated in patients with CHB, demonstrating consistent dose-dependent pharmacodynamic induction of ISG15 without significant systemic induction of IFNα expression or related symptoms. However, no significant HBsAg declines were observed., Lay Summary: In a phase II study, vesatolimod, an oral, once-weekly, experimental immune-activating drug for the treatment of hepatitis B virus (HBV), is safe and well-tolerated in chronic HBV patients who are virally suppressed on oral antiviral treatment. Despite demonstrating on-target biomarker responses in patients, no significant declines in hepatitis B surface antigen were observed. Clinical Trial Number: GS-US-283-1059; NCT 02166047., (Copyright © 2017 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Objectives: This phase II, open-label study was designed to evaluate the response rate to the polo-like kinase 1 (Plk-1) inhibitor BI 2536 in patients with sensitive-relapsed small cell lung cancer (SCLC). Secondary endpoints included progression-free survival (PFS), overall survival (OS), duration of response, and safety., Materials and Methods: Patients were treated with the recommended phase II dose of 200mg of BI 2536 intravenously every 21days. This was a two-stage design with an early stopping rule in place if responses were not seen in at least 2 of the first 18 enrolled patients., Results and Conclusion: Twenty-three patients were enrolled in the study and 21 patients were evaluable for response. No responses were observed and all 23 patients have progressed. The median PFS was 1.4 months. Treatment was generally well tolerated and the most frequent adverse events were neutropenia, fatigue, nausea, vomiting, and constipation. BI 2536 is not effective in the treatment of sensitive relapsed SCLC. The criteria for expanding the trial to the second stage were not achieved, and the study was terminated for a lack of efficacy., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Purpose: This trial evaluated the maximum tolerated dose (MTD), safety, pharmacokinetics, and clinical effects of volasertib, a selective Polo-like kinase inhibitor that induces mitotic arrest and apoptosis, in Japanese patients with advanced solid tumors (NCT01348347; 1230.15)., Methods: In this phase I, open-label, dose-escalation trial, sequential patient cohorts (3 + 3 dose-escalation design) received volasertib (200-350 mg) as a single dose by intravenous infusion over 2 h on day 1 every 21 days until disease progression or unacceptable toxicity. The primary endpoint was the MTD of volasertib in Japanese patients with an advanced solid tumor; secondary endpoints included safety, pharmacokinetics, and clinical benefit., Results: Fifteen patients with an advanced solid tumor were treated. Dose-limiting toxicities of grade 4 neutropenia for ≥7 days and grade 4 thrombocytopenia were both experienced by 2/6 patients in the 350 mg cohort. The MTD of volasertib in Japanese patients was 300 mg. The most common (≥3 patients) drug-related non-hematologic adverse events included fatigue, decreased appetite, and nausea. Exposure to volasertib and its metabolite increased with increasing doses. A partial response in a patient with gastric cancer and stable disease in eleven patients were observed., Conclusions: Volasertib had a manageable safety profile up to the MTD determined as 300 mg. Exposure to volasertib and its metabolite increased with increasing doses. The safety profile of volasertib in Japanese patients is comparable with those previously obtained in Caucasian patients. These data support enrollment of Japanese patients in global clinical trials without dose modification.

This phase I trial conducted in Japanese patients with acute myeloid leukemia evaluated the safety, maximum tolerated dose and pharmacokinetics of volasertib (BI 6727), a selective Polo-like kinase inhibitor. The primary endpoints were the maximum tolerated dose of volasertib and the incidence of dose-limiting toxicities. Secondary endpoints were best response and remission duration. Other endpoints included safety and pharmacokinetics. Patients who were ineligible for standard induction therapy or with relapsed or refractory disease received volasertib monotherapy as a 2-h infusion on days 1 and 15 of a 28-day cycle, with dose escalation following a 3 + 3 design. A total of 19 patients were treated with three volasertib doses: 350, 400 and 450 mg. One patient receiving volasertib 450 mg reported a dose-limiting toxicity of grade 4 abnormal liver function test and 450 mg was determined as the maximum tolerated dose. The most frequently reported adverse events were febrile neutropenia (78.9%), decreased appetite (42.1%), nausea and rash (36.8% each), and sepsis, fatigue, hypokalemia, stomatitis and epistaxis (26.3% each). Best responses were complete remission (n = 3), complete remission with incomplete blood count recovery (n = 3) and partial remission (n = 1). The median remission duration of the six patients with complete remission or complete remission with incomplete blood count recovery was 85 days (range 56-358). Volasertib exhibited multi-compartmental pharmacokinetic behavior with a fast distribution after the end of infusion followed by slower elimination phases. Volasertib monotherapy was clinically manageable with acceptable adverse events and anti-leukemic activity., (© 2015 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.)

Unlabelled: Second-line therapy options that improve survival for patients with advanced non-small-cell lung cancer (NSCLC) are needed. This randomized, phase II trial (n [ 143) investigated volasertib monotherapy or in combination with pemetrexed compared with pemetrexed monotherapy in patients with NSCLC whose disease had progressed after previous platinum-based chemotherapy. The combination of volasertib with pemetrexed did not improve efficacy compared with pemetrexed monotherapy., Introduction: Volasertib is a potent, selective, cell cycle kinase inhibitor that induces mitotic arrest and apoptosis by targeting Polo-like kinase. In this study we compared volasertib, volasertib with pemetrexed, and pemetrexed alone in patients with advanced non-small-cell lung cancer (NSCLC) whose disease progressed after first-line platinum-based chemotherapy., Patients and Methods: A run-in phase (n = 12) was used to determine whether volasertib could be combined in full dose with pemetrexed 500 mg/m(2). Subsequent patients were randomized to volasertib (n = 37), volasertib with pemetrexed (n = 47), or pemetrexed (n = 47) administered on day 1 every 21 days. The primary end point was progression-free survival (PFS); secondary end points included objective response rate and pharmacokinetics., Results: Volasertib 300 mg was chosen for the randomized phase. Recruitment to single-agent volasertib was stopped early because of lack of efficacy. Median PFS was 5.3 months with pemetrexed compared with 3.3 months with volasertib with pemetrexed (hazard ratio [HR], 1.141; 95% confidence interval [CI], 0.73-1.771) and 1.4 months with volasertib (HR, 2.045; 95% CI, 1.27-3.292). ORRs were 10.6% with pemetrexed, 21.3% for volasertib with pemetrexed, and 8.1% with volasertib. The most common all-grade related adverse events (pemetrexed/volasertib with pemetrexed/volasertib) were: fatigue (28 [61%]/27 [59%]/11 [31%]), nausea (21 [46%]/19 [41%]/0 [0%]), decreased apetite (14 [31%]/13 [28%]/2 [6%]), neutropenia (4 [9%]/8 [17%]/9 [25%]), rash (9 [20%]/8 [17%]/2 [6%]), vomiting (6 [13%]/13 [28%]/0 [0%]), and diarrhea (8 [17%]/11 [24%]/0 [0%]). Pharmacokinetics analyses showed no drug-drug interactions between volasertib and pemetrexed., Conclusion: For treatment in the second-line for advanced or metastatic NSCLC, the combination of volasertib with standard pemetrexed did not increase toxicity significantly but also did not improve efficacy compared with single-agent pemetrexed., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Purpose: To determine the maximum tolerated dose (MTD) of volasertib, a Polo-like kinase inhibitor, combined with afatinib, an oral irreversible ErbB family blocker, in patients with advanced solid tumors (NCT01206816; Study 1230.20)., Methods: Patients with advanced non-resectable and/or metastatic disease following failure of conventional treatment received intravenous volasertib 150-300 mg on day 1 every 21 days, combined with oral afatinib 30-40 mg on days 2-21 of a 3-week cycle (Schedule A), or 50-90 mg on days 2-6 of a 3-week cycle (Schedule B). The primary objective was to determine the MTD of volasertib in combination with afatinib., Results: Fifty-seven patients (Schedule A, N = 29; Schedule B, N = 28) were treated. The MTDs were volasertib 300 mg plus afatinib 30 mg days 2-21 and 70 mg days 2-6 of a 3-week cycle for Schedules A and B, respectively. The most common Grade 3/4 adverse events were neutropenia (31.0 %), diarrhea (13.8 %), and thrombocytopenia (10.3 %) in Schedule A; neutropenia (39.3 %), thrombocytopenia (35.7 %), hypokalemia (14.3 %), febrile neutropenia, and nausea (each 10.7 %) in Schedule B. The best overall response was two partial responses (6.9 %; both in Schedule A); eight patients in each schedule achieved stable disease. Volasertib showed multi-exponential pharmacokinetic (PK) behavior; co-administration of volasertib and afatinib had no significant effects on the PK profile of either drug., Conclusions: Volasertib combined with afatinib had manageable adverse effects and limited antitumor activity in this heavily pretreated population.

Background: This trial evaluated the maximum tolerated dose (MTD), safety, pharmacokinetics, and activity of volasertib, a selective Polo-like kinase 1 inhibitor that induces mitotic arrest and apoptosis, combined with cisplatin or carboplatin in patients with advanced/metastatic solid tumors (NCT00969761; 1230.6)., Methods: Sequential patient cohorts (3 + 3 dose-escalation design) received a single infusion of volasertib (100-350 mg) with cisplatin (60-100 mg/m(2)) or carboplatin (area under the concentration versus time curve [AUC]4-AUC6) on day 1 every 3 weeks for up to six cycles. Sixty-one patients received volasertib/cisplatin (n = 30) or volasertib/carboplatin (n = 31) for a median of 3.5 (range, 1-6) and 2.0 (range, 1-6) treatment cycles, respectively., Results: The most common cycle 1 dose-limiting toxicities (DLTs) were thrombocytopenia, neutropenia and fatigue. MTDs (based on cycle 1 DLTs) were determined to be volasertib 300 mg plus cisplatin 100 mg/m(2) and volasertib 300 mg plus carboplatin AUC6. Co-administration did not affect the pharmacokinetics of each drug. Partial responses were observed in two patients in each arm. Stable disease was achieved in 11 and six patients treated with volasertib/cisplatin and volasertib/carboplatin, respectively., Conclusions: Volasertib plus cisplatin or carboplatin at full single-agent doses was generally manageable and demonstrated activity in heavily pretreated patients with advanced solid tumors.

Background: GS-9620 is a potent oral agonist of toll-like receptor 7, a key modulator of the innate immune response. In healthy volunteers, low doses of GS-9620 (2, 4 and 6 mg) induced significant expression of peripheral interferon-stimulated-gene (ISG) mRNA in the absence of detectable serum interferon-α and systemic adverse events (AEs). We evaluated the safety, pharmacokinetics and pharmacodynamics of GS-9620 in treatment-naive patients chronically infected with HCV genotype 1., Methods: In this double-blind, placebo-controlled study, 51 patients were randomized 5:1 (active:placebo) to receive either a single dose or two once-weekly doses of GS-9620 at four dose levels (0.3, 1, 2 and 4 mg) or placebo. Pharmacodynamic assessments included peripheral ISG15 mRNA expression, serum interferon-α and interferon-γ-inducible protein (IP)-10 levels and HCV RNA quantification., Results: GS-9620 was well-tolerated at all doses. Most AEs were mild or moderate in severity. GS-9620 exhibited dose-linear pharmacokinetics with a median half-life in plasma of 18 h. Transient, dose-dependent ISG15 induction was observed at 1, 2 and 4 mg, with peak mean fold change within 48 h followed by a decline to baseline levels within 7 days of dosing. Serum interferon-α induction post-baseline was detected in 16.7% (8/48) of patients. No clinically significant reductions in HCV RNA were observed., Conclusions: GS-9620 was safe, well-tolerated and biologically active in patients with HCV infection. Induction of ISG15 occurred in the absence of detectable serum interferon-α or systemic AEs in most patients, supporting a pre-systemic mechanism of action. ClinicalTrials.gov identifier: NCT01591668.

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 + volasertib 350 mg IV days 1 + 15 every 4 weeks. Response rate (complete remission and complete remission with incomplete blood count recovery) was higher for LDAC + volasertib vs LDAC (31.0% vs 13.3%; odds ratio, 2.91; P = .052). Responses in the LDAC + 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 + volasertib compared with LDAC (5.6 vs 2.3 months; hazard ratio, 0.57; 95% confidence interval, 0.35-0.92; P = .021); median overall survival was 8.0 vs 5.2 months, respectively (hazard ratio, 0.63; 95% confidence interval, 0.40-1.00; P = .047). LDAC + 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 + 90. This study was registered at www.clinicaltrials.gov as #NCT00804856., (© 2014 by The American Society of Hematology.)

Background: Polo-like kinase 1 (Plk1) has an important role in mitosis. Volasertib (BI 6727), a potent and selective cell cycle kinase inhibitor, induces mitotic arrest and apoptosis by targeting Plk; this phase I study sought to determine its maximum tolerated dose (MTD) in Asian patients with advanced solid tumours., Methods: Patients were enrolled simultaneously into two 3-week schedules of volasertib: a 2-h infusion on day 1 (schedule A) or days 1 and 8 (schedule B). Dose escalation followed a 3+3 design. The MTD was determined based on dose-limiting toxicities (DLT) in the first treatment course., Results: Among 59 treated patients, the most common first course DLTs were reversible thrombocytopenia, neutropenia and febrile neutropenia; MTDs were 300 mg for schedule A and 150 mg for schedule B. Volasertib exhibited multi-exponential pharmacokinetics (PK), a long terminal half-life of ∼135 h, a large volume of distribution (>3000 l), and a moderate clearance. Partial responses were observed in two pre-treated patients (ureteral cancer; melanoma). Volasertib was generally well tolerated, with an adverse event profile consistent with its antimitotic mode of action and a favourable PK profile., Conclusions: These data support further development of volasertib and a harmonised dosing for Asian and Caucasian patients.

Significant advances in cancer treatment have resulted from the targeted cancer therapy by understanding the process of malignant transformation. Polo-like kinase 1 (PLK1) has been investigated as a target for cancer therapy for several years. Recently, anticancer drug candidates targeting PLK1 have been developed. To investigate the significance of PLK1 inhibitors in cancer patients, the current clinical statuses of PLK1 inhibitors including BI 2536, volasertib, and GSK461364A were analyzed. Monotherapy with BI 2536, the first human study of PLK1 inhibitors, has been terminated now, but its combinational study is still available in several solid tumors. The second-generation PLK1 inhibitor volasertib has an improved pharmacokinetic profile, safety, and efficacy, which is currently being developed under phase I/II. GSK461364 has shown a greater sensitive antitumor effect in p53-mutated cancer compared with that of p53-wild type cancer cells in a preclinical study. However, it has to be coadministered with an anticoagulator because of the high incidence of venous thrombotic emboli in clinical studies. PLK1 inhibitors showed a favorable pharmacokinetic profile, safety, and efficacy in patients with solid tumors. Further investigation with the use of PLK1 inhibitors in cancer patients who have mutated p53 or Ras and a high level of PLK1 as biomarkers is needed to consider the context and evaluation criteria of therapy.

Background: GS-9620 is a novel oral agonist of Toll-like receptor 7 (TLR7) in development for the treatment of chronic viral hepatitis. TLR7 is a highly conserved innate immune receptor expressed primarily on plasmacytoid dendritic cells and B lymphocytes. The aim of this double-blind, placebo-controlled, single ascending-dose study was to investigate the safety, tolerability, pharmacokinetics and pharmacodynamics of GS-9620 in healthy volunteers., Methods: In total, 75 healthy volunteers (8 subjects in each of the 10 cohorts; 5 subjects participated in two cohorts) were randomized (6:2) to receive a single dose of GS-9620 (0.3, 1, 2, 4, 6, 8 or 12 mg) or placebo., Results: GS-9620 was well-absorbed and well-tolerated in oral doses up to 12 mg. Minimal treatment-related adverse events were seen at doses up to 8 mg. Serum interferon (IFN)-α was only detected in subjects who received 8 or 12 mg doses, and the adverse event profile at 8 and 12 mg doses was generally consistent with that associated with IFN-α exposure (flu-like symptoms), consistent with the mechanism of TLR7 agonism. All adverse events resolved within 72 h. Induction of chemokines/cytokines and IFN-stimulated genes were seen at GS-9620 doses ≥ 2 mg, well below doses that induced serum IFN-α or led to clinical adverse events., Conclusions: GS-9620 demonstrates safety and pharmacodynamic activity at doses up to 12 mg. Pharmacodynamic activity is seen before adverse events, suggesting the potential for induction of an antiviral response without systemic adverse events in subjects with chronic viral hepatitis.

Background: BI 2536, a novel Polo-like kinase 1 inhibitor, was assessed in patients with unresectable advanced exocrine adenocarcinoma of the pancreas., Methods: The study employed a two-stage design. Randomised first-line patients received BI 2536 200 mg on day 1 (n=43) or 60 mg on days 1-3 (n=43) every 21 days. Recruitment of second-line patients was planned for a second stage dependent on an interim analysis demonstrating ≥ 2 responses in the first 18 evaluable patients following 12 weeks of treatment and/or tumour control ≥ 12 weeks in 5 patients per schedule. Primary end point was objective response rate (ORR)., Results: By independent review, ORR was 2.3% (all partial) and 24.4% had stable disease as confirmed best response. The second stage was not initiated. Median overall and progression-free survivals were 149 (95% confidence interval (CI), 91-307) and 46 days (95% CI, 44-56). Most common drug-related adverse events were neutropenia (37.2%), leukopenia (29.1%), fatigue (29.1%) and nausea (22.1%); most common grade 3/4-related events were neutropenia (36.0%), leukopenia (27.9%) and thrombocytopenia (8.1%)., Conclusion: Given the low ORR and poor survival, further development of BI 2536 monotherapy is not warranted in this population.

Purpose: The aim of this investigation was to compare the performance of a commonly used semi-mechanistic model for drug-related neutropenia with other semi-mechanistic models published in the literature., Methods: After their implementation in NONMEM VI, five semi-mechanistic models were assessed using the pharmacokinetic and absolute neutrophil count data obtained from 95 patients with non-small cell lung cancer receiving either 200 mg on day 1 or 50 or 60 mg on days 1, 2 and 3 of a 21-day treatment course with the new Plk-1 inhibitor BI 2536. The model performance was compared by means of predictive (visual and numerical) checks, precision in the parameter estimates and objective function-based measures. Details of model parameterization, model stability and run times are also provided., Results: The time course of the drug plasma concentrations was described by a three compartment model with a first-order elimination rate. With respect to neutropenia, all models were successfully implemented in NONMEM and provided reasonable fits for the median (although not all models described all percentiles of the data well), and in general precise parameter estimates., Conclusion: In the current evaluation performed in a single drug, none of the models showed superior performance compared to the most commonly used model first described by Friberg et al. (J Clin Oncol 20:4713-4721, 2002).

Purpose: This phase I, open-label, dose-escalation study investigated the maximum tolerated dose (MTD) of BI 2536, a small-molecule polo-like kinase (Plk)-1 inhibitor, in two treatment schedules in patients with advanced solid tumors. Secondary objectives included evaluation of safety, efficacy, and pharmacokinetics., Experimental Design: Patients received a single i.v. dose of BI 2536 as a 1-hour infusion on days 1 and 8 or a single 24-hour infusion on day 1 of each 21-day treatment course. MTD determination was based on dose-limiting toxicities., Results: Forty-four and 26 patients received each treatment schedule, respectively. The MTD of BI 2536 in the day 1 and 8 schedule was 100 mg per administration (200 mg per course). The MTD for the second dosing schedule was not determined; a 225-mg dose was well tolerated. The most frequently reported treatment-related nonhematologic adverse events were gastrointestinal events and fatigue. Hematotoxicity as the most relevant side effect was similar in both schedules; neutropenia grades 3 and 4 were observed in 16 patients (36.4%) of the day 1 and 8 schedule and 13 patients (50%) of the 24-hour infusion. Fourteen patients (32%) treated in the day 1 and 8 dosing schedule had a best overall response of stable disease. Plasma concentrations of BI 2536 increased dose proportionally, with no relevant accumulation of exposure in the day 1 and 8 dosing schedule. The average terminal half-life was 50 hours., Conclusions: BI 2536 administered in either treatment schedule has adequate safety in patients with advanced solid tumors, warranting further clinical investigation of polo-like kinase-1 inhibitors., (©2010 AACR.)

Purpose: (1) To describe the neutropenic response of BI 2536 a polo-like kinase 1 inhibitor in patients with cancer using a semi-mechanistic model. (2) To explore by simulations (a) the neutropenic effects for the maximum tolerated dose (MTD) and the dose at which dose-limiting toxicity occurred, (b) the possibility to reduce the cycle duration without increasing neutropenia substantially, and (c) the impact of the initial absolute neutrophil count (ANC) on the degree of neutropenia for different doses., Experimental Design: BI 2536 was administered as intravenous infusion over 60 min in the dose range from 25 to 250 mg. Three different administration schedules were explored: (a) day 1, (b) days 1, 2, and 3 or (c) days 1 and 8 within a 3 week treatment cycle. BI 2536 plasma concentrations and ANC obtained during the first treatment cycle from 104 patients were analysed using the population approach with NONMEM VI., Results: Neutropenia was described by a semi-mechanistic model resembling proliferation at the stem cell compartment, maturation, degradation, and homeostatic regulation. BI 2536 acts decreasing proliferation rate. Simulations showed that (1) all MTD doses showed an acceptable risk of neutropenia, (2) when BI 2536 is given as 200 mg single administration, cycle duration can be reduced from 3 to 2 weeks, and (3) baseline ANC might be considered to individualise the dose of BI 2536., Conclusions: A semi-mechanistic population model was applied to describe the neutropenic effects of BI 2536. The model was used for simulations to support further clinical development.

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 18years old, had a good performance status, adequate bone marrow, renal and liver function, measurable progressive disease and had completed other relevant systemic treatments >4weeks ago. BI 2536 200-250mg 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., (Copyright 2010 Elsevier Ltd. All rights reserved.)

Medicinal crystalluria is often difficult to recognize and identify. Whether due to therapeutic overdoses or individual susceptibility, the diagnosis is always important. 70% of the drugs involved in crystalluria can induce kidney stones or promote their growth. In addition, approximately one medicinal crystalluria out of ten is clinically or biologically accompanied by kidney failure. On the basis of 59 cases of medicinal crystalluria, the means of identification, the molecules involved and the frequency of these iatrogenic crystalluria is discusses.