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1.
Clin Pharmacol Ther ; 2024 May 16.
Artículo en Inglés | MEDLINE | ID: mdl-38752712

RESUMEN

The landscape of oncology drug development has witnessed remarkable advancements over the last few decades, significantly improving clinical outcomes and quality of life for patients with cancer. Project Optimus, introduced by the U.S. Food and Drug Administration, stands as a groundbreaking endeavor to reform dose selection of oncology drugs, presenting both opportunities and challenges for the field. To address complex dose optimization challenges, an Oncology Dose Optimization IQ Working Group was created to characterize current practices, provide recommendations for improvement, develop a clinical toolkit, and engage Health Authorities. Historically, dose selection for cytotoxic chemotherapeutics has focused on the maximum tolerated dose, a paradigm that is less relevant for targeted therapies and new treatment modalities. A survey conducted by this group gathered insights from member companies regarding industry practices in oncology dose optimization. Given oncology drug development is a complex effort with multidimensional optimization and high failure rates due to lack of clinically relevant efficacy, this Working Group advocates for a case-by-case approach to inform the timing, specific quantitative targets, and strategies for dose optimization, depending on factors such as disease characteristics, patient population, mechanism of action, including associated resistance mechanisms, and therapeutic index. This white paper highlights the evolving nature of oncology dose optimization, the impact of Project Optimus, and the need for a tailored and evidence-based approach to optimize oncology drug dosing regimens effectively.

2.
Clin Ther ; 42(11): 2214-2224, 2020 11.
Artículo en Inglés | MEDLINE | ID: mdl-33139055

RESUMEN

PURPOSE: This drug-drug interaction study determined whether the metabolism and distribution of the Polo-like kinase 1 inhibitor, volasertib, is affected by co-administration of the P-glycoprotein and cytochrome P-450 3A4 inhibitor, itraconazole. METHODS: This was an uncontrolled, open-label, fixed-sequence trial of two 21-day treatment cycles in patients with various solid tumors. In cycle 1 (test), eligible patients were administered volasertib (day 1) plus itraconazole (days -3 to 15). In cycle 2 (reference), patients received volasertib monotherapy. The primary end point was the influence of co-administration of itraconazole on the pharmacokinetic profile (AUC0-tz; Cmax) of volasertib and its main metabolite, CD 10899, compared with that of volasertib monotherapy. Other end points included tolerability and preliminary therapeutic efficacy. FINDINGS: Concurrent administration of itraconazole resulted in a slight reduction in the AUC0-tz (geometric mean ratio, 93.6%; 90% CI, 82.1%-106.8%) and a 20% reduction in Cmax (geometric mean ratio, 79.4%; 90% CI, 64.9%-97.1%) of volasertib compared with monotherapy. Of note, concurrent administration of itraconazole + volasertib had no effect on the AUC0-∞ of volasertib. More patients reported at least one drug-related adverse event in cycle 1 than in cycle 2 (75% vs 71%). The most commonly reported drug-related adverse events (cycles 1 and 2) were thrombocytopenia (68% and 33%, respectively), leukopenia (50% and 46%), and anemia (36% and 33%). No objective responses were observed. Stable disease was observed in 25 of 28 patients (89%). IMPLICATIONS: While there was no clear evidence of a pharmacokinetic interaction between volasertib and itraconazole, co-administration reduced the tolerability of volasertib. Clinicaltrials.gov identifier: NCT01772563.


Asunto(s)
Antineoplásicos/administración & dosificación , Neoplasias/tratamiento farmacológico , Adulto , Anciano , Antineoplásicos/uso terapéutico , Proteínas de Ciclo Celular/antagonistas & inhibidores , Interacciones Farmacológicas , Femenino , Humanos , Itraconazol/administración & dosificación , Itraconazol/farmacología , Masculino , Persona de Mediana Edad , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Proto-Oncogénicas/antagonistas & inhibidores , Pteridinas/administración & dosificación , Quinasa Tipo Polo 1
3.
Ther Innov Regul Sci ; 52(4): 416-422, 2018 07.
Artículo en Inglés | MEDLINE | ID: mdl-29714574

RESUMEN

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.


Asunto(s)
Síndrome de QT Prolongado/diagnóstico , Inhibidores de Proteínas Quinasas/efectos adversos , Pteridinas/efectos adversos , Ensayos Clínicos como Asunto , Drogas en Investigación , Electrocardiografía , Humanos , Síndrome de QT Prolongado/inducido químicamente , Estudios Prospectivos , Inhibidores de Proteínas Quinasas/administración & dosificación , Pteridinas/administración & dosificación , Proyectos de Investigación
4.
Clin Pharmacokinet ; 57(3): 379-392, 2018 03.
Artículo en Inglés | MEDLINE | ID: mdl-28631179

RESUMEN

BACKGROUND: Volasertib, a potent and selective polo-like kinase inhibitor, has shown to increase response rates and improve survival with a clinically manageable safety profile, administered alone and in combination with cytarabine in patients with acute myeloid leukaemia. OBJECTIVES: The objectives of this analysis were to describe the pharmacokinetics of volasertib and cytarabine, administered as single agents or in combination. METHODS: Three thousand, six hundred and six plasma volasertib concentrations from 501 patients receiving either volasertib alone, or in combination with cytarabine, and 826 plasma cytarabine concentrations from 650 patients receiving cytarabine as multiple subcutaneous injections per cycle either alone, or in combination with volasertib, were analysed using NONMEM Version 7.3. Covariates evaluated included demographic and disease-related parameters. RESULTS: The pharmacokinetics of volasertib were found to be dose independent from 150 to 550 mg. Body surface area and ethnicity showed significant effects in all the patients. This is reflected as an increase in drug exposure for Japanese patients, although this finding has to be interpreted with caution because only 7% of patients were part of that population group. Volasertib showed low-to-mild inter-individual variability in total clearance. For the case of cytarabine, its pharmacokinetics was affected by body surface area. Finally, volasertib and cytarabine did not influence the pharmacokinetic characteristics of each other. CONCLUSIONS: The pharmacokinetics of volasertib in patients with acute myeloid leukaemia alone or in combination with cytarabine is predictable and associated with low-to-mild patient variability with the exception of the high variability associated with the volume of distribution of the central compartment, having no effect on the area under the plasma concentration-time curve.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Leucemia Mieloide Aguda/tratamiento farmacológico , Pteridinas/administración & dosificación , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Área Bajo la Curva , Superficie Corporal , Citarabina/administración & dosificación , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pteridinas/farmacocinética , Distribución Tisular
5.
Lung Cancer ; 104: 126-130, 2017 02.
Artículo en Inglés | MEDLINE | ID: mdl-28212994

RESUMEN

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.


Asunto(s)
Proteínas de Ciclo Celular/antagonistas & inhibidores , Neoplasias Pulmonares/tratamiento farmacológico , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Proto-Oncogénicas/antagonistas & inhibidores , Pteridinas/administración & dosificación , Carcinoma Pulmonar de Células Pequeñas/tratamiento farmacológico , Administración Intravenosa , Adulto , Anciano , Proteínas de Ciclo Celular/efectos adversos , Proteínas de Ciclo Celular/uso terapéutico , Supervivencia sin Enfermedad , Femenino , Humanos , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia , Estadificación de Neoplasias , Proteínas Serina-Treonina Quinasas/efectos adversos , Proteínas Serina-Treonina Quinasas/uso terapéutico , Proteínas Proto-Oncogénicas/efectos adversos , Proteínas Proto-Oncogénicas/uso terapéutico , Pteridinas/efectos adversos , Pteridinas/farmacología , Recurrencia , Carcinoma Pulmonar de Células Pequeñas/patología , Fumar/epidemiología , Insuficiencia del Tratamiento , Resultado del Tratamiento , Quinasa Tipo Polo 1
6.
Blood ; 124(9): 1426-33, 2014 Aug 28.
Artículo en Inglés | MEDLINE | ID: mdl-25006120

RESUMEN

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.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica , Citarabina/administración & dosificación , Leucemia Mieloide Aguda/tratamiento farmacológico , Pteridinas/administración & dosificación , Factores de Edad , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Contraindicaciones , Citarabina/efectos adversos , Supervivencia sin Enfermedad , Femenino , Humanos , Quimioterapia de Inducción , Estimación de Kaplan-Meier , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Masculino , Persona de Mediana Edad , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/farmacocinética , Pteridinas/efectos adversos , Pteridinas/farmacocinética , Resultado del Tratamiento
7.
Cancer ; 120(7): 976-82, 2014 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-24339028

RESUMEN

BACKGROUND: Polo-like kinases (Plks) control multiple steps during the cell cycle, and Plk1 is overexpressed in urothelial cancer (UC). Volasertib (BI 6727), a Plk inhibitor, has demonstrated antitumor activity in several malignancies, including UC. In this phase 2 trial, the authors investigated volasertib as a second-line treatment in advanced/metastatic UC. METHODS: Patients who progressed within 2 years of 1 prior chemotherapy regimen received 300 mg volasertib on day 1 every 3 weeks. The dose was escalated to 350 mg in cycle 2 if volasertib was tolerated in cycle 1. The primary endpoint was tumor response, which was assessed every 6 weeks; secondary endpoints were progression-free survival, overall survival, duration of response, safety, and pharmacokinetics. RESULTS: Fifty patients were enrolled, and the median patient age was 68.5 years (range, 52-83 years). All patients had received prior platinum, 94% of patients had relapsed ≤2 years after prior therapy, 36% had liver metastases, and 54% had lung metastases. The median number of treatment cycles was 2 (range, 1-27 treatment cycles), and 23 patients were dose escalated at cycle 2. Seven patients (14%) had a partial response, 13 (26%) had stable disease, and 30 (60%) progressed within 6 weeks. The median response duration was 41 weeks (range, 29.1-77.3 weeks). The median progression-free survival was 1.4 months, and the median overall survival was 8.5 months. The most frequent grade 3 and 4 adverse events were neutropenia (28%), thrombocytopenia (20%), and anemia (16%). No cumulative toxicity was observed. CONCLUSIONS: Volasertib as second-line treatment for advanced/metastatic UC had an acceptable safety profile but demonstrated insufficient antitumor activity for further evaluation as a monotherapy.


Asunto(s)
Pteridinas/uso terapéutico , Neoplasias Urológicas/tratamiento farmacológico , Anciano , Anciano de 80 o más Años , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapéutico , Supervivencia sin Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Inhibidores de Proteínas Quinasas/farmacocinética , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Pteridinas/farmacocinética , Resultado del Tratamiento , Neoplasias Urológicas/enzimología , Neoplasias Urológicas/metabolismo , Neoplasias Urológicas/patología
8.
Br J Haematol ; 163(2): 214-22, 2013 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-24033250

RESUMEN

Polo-like kinases (Plks) play an important role in cell cycle checkpoint controls and are over-expressed in acute myeloid leukaemia (AML). BI 2536, a novel Plk inhibitor, induces mitotic arrest and apoptosis. In this phase I/II trial of BI 2536 in 68 elderly patients with relapsed/refractory AML, three schedules were investigated (day 1, days 1-3, and days 1 + 8). Maximum tolerated dose was 350 and 200 mg in the day 1 and days 1 + 8 schedules, respectively. The day 1-3 schedule appeared equivalent to the day 1 schedule and was discontinued early. BI 2536 exhibited multi-compartmental pharmacokinetic behaviour. The majority of patients showed an increase of bone marrow cells in G2/M with a characteristic pattern of mitotic catastrophe. The overall response rate in the day 1 and day 1 + 8 schedules was 9% (5/54) with 2 complete and 3 partial responses. The majority of drug-related adverse events grade ≥3 were haematological. Taken together, Plk inhibition induced cell cycle arrest in AML blasts in vivo and BI 2536 monotherapy showed modest clinical activity in this poor prognosis patient group.


Asunto(s)
Antineoplásicos/uso terapéutico , Proteínas de Ciclo Celular/antagonistas & inhibidores , Leucemia Mieloide Aguda/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Proto-Oncogénicas/antagonistas & inhibidores , Pteridinas/uso terapéutico , Factores de Edad , Anciano , Anciano de 80 o más Años , Antineoplásicos/farmacología , Esquema de Medicación , Femenino , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/mortalidad , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Inhibidores de Proteínas Quinasas/farmacología , Pteridinas/farmacología , Recurrencia , Resultado del Tratamiento , Quinasa Tipo Polo 1
9.
Clin Lung Cancer ; 14(1): 19-27, 2013 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-22658814

RESUMEN

INTRODUCTION: BI 2536 is a potent, highly selective inhibitor of polo-like kinase (Plk) 1. This open-label, phase I study investigated the maximum tolerated dose (MTD), safety, efficacy, and pharmacokinetics (PK) of BI 2536 IV in combination with standard-dose pemetrexed in previously treated advanced or metastatic non-small-cell lung cancer. PATIENTS AND METHODS: A standard 3 + 3 design was used. The patients received 500 mg/m(2) pemetrexed and escalating doses of BI 2536 on day 1 every 3 weeks. The primary objective was the MTD of BI 2536 combined with pemetrexed. Secondary endpoints were response rate (Response Evaluation Criteria in Solid Tumors), overall safety, and PK. RESULTS: Forty-one patients received BI 2536 (100-325 mg). Two dose-limiting toxicities (DLT) occurred at BI 2536 325 mg (grade 3 pruritus and rash; grade 4 neutropenia). Therefore, the MTD for BI 2536 in combination with pemetrexed was 300 mg. After expanding the MTD dose level, 3 additional patients experienced DLTs, which resulted in expansion of the 250 mg cohort, in which 4 of the 13 additional patients experienced DLTs. Therefore, the recommended dose of BI 2536 was 200 mg. Most frequently reported drug-related adverse events were fatigue (71%), nausea (37%), and rash (34%). Two patients had durable confirmed partial responses; 21 (54%) patients had stable disease after the treatment cycle 2. PK analysis showed that BI 2536 and pemetrexed exposure were not altered when coadministered. CONCLUSION: BI 2536 200 mg combined with standard-dose pemetrexed has an acceptable safety profile in relapsed non-small-cell lung cancer. The antitumor activity observed is encouraging and supports further investigation of Plk inhibitors.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Administración Intravenosa , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Proteínas de Ciclo Celular/antagonistas & inhibidores , Supervivencia sin Enfermedad , Erupciones por Medicamentos/etiología , Interacciones Farmacológicas , Inhibidores Enzimáticos/administración & dosificación , Fatiga/inducido químicamente , Femenino , Glutamatos/administración & dosificación , Guanina/administración & dosificación , Guanina/análogos & derivados , Humanos , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Náusea/inducido químicamente , Neutropenia/inducido químicamente , Pemetrexed , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Proto-Oncogénicas/antagonistas & inhibidores , Prurito/inducido químicamente , Pteridinas/administración & dosificación , Resultado del Tratamiento , Quinasa Tipo Polo 1
10.
Eur J Clin Pharmacol ; 69(3): 327-39, 2013 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-22782539

RESUMEN

PURPOSE: To evaluate the pharmacokinetic and pharmacodynamic effects of concomitant administration of single loading doses of clopidogrel or multiple doses of clopidogrel with multiple doses of dabigatran etexilate. METHODS: This was an open-label trial in healthy male subjects. In part 1 (pilot, n = 8) and part 3 (n = 12), a single dose of clopidogrel (300 or 600 mg, respectively) was given concomitantly with dabigatran etexilate at steady state; part 2 was a randomized, multiple-dose, crossover study with the test treatment being clopidogrel at steady state [300 mg loading dose on day 1, then 75 mg once daily (qd)] with concomitant dabigatran. RESULTS: Bioavailability was moderately increased when a loading dose of clopidogrel (300 mg in part 1 and 600 mg in part 3) was administered concomitantly with dabigatran etexilate 150 mg twice daily (bid). Test/reference ratios for AUC(τ,ss) were 135% (90% CI 107-169%) and 132% (90% CI 112-156%), respectively. Steady-state dosing of clopidogrel 75 mg qd and dabigatran etexilate 150 mg bid (part 2) demonstrated minor effects on dabigatran pharmacokinetics (AUC(τ,ss) ratio test/reference: 91.9%, 90% CI 78.7-107%) or its pharmacokinetic/pharmacodynamic relationships (activated partial thromboplastin time, ecarin clotting time, thrombin time). Similarly, clopidogrel bioavailability remained unchanged by chronic administration of dabigatran etexilate (part 3: ratio test/reference for AUC(0-24) was 103%; 90% CI 80.3-131%), as did its pharmacodynamic effects on the inhibition of platelet aggregation. CONCLUSIONS: When given concomitantly, dabigatran etexilate and clopidogrel at clinically relevant doses did not appear to have significant effects on the pharmacokinetic and pharmacodynamic profiles of either agent.


Asunto(s)
Antitrombinas/farmacocinética , Bencimidazoles/farmacocinética , Coagulación Sanguínea/efectos de los fármacos , Inhibidores de Agregación Plaquetaria/farmacocinética , Agregación Plaquetaria/efectos de los fármacos , Piridinas/farmacocinética , Ticlopidina/análogos & derivados , Adulto , Análisis de Varianza , Antitrombinas/administración & dosificación , Área Bajo la Curva , Bencimidazoles/administración & dosificación , Disponibilidad Biológica , Tiempo de Sangría , Clopidogrel , Estudios Cruzados , Dabigatrán , Interacciones Farmacológicas , Monitoreo de Drogas/métodos , Quimioterapia Combinada , Alemania , Humanos , Masculino , Tasa de Depuración Metabólica , Tiempo de Tromboplastina Parcial , Proyectos Piloto , Inhibidores de Agregación Plaquetaria/administración & dosificación , Piridinas/administración & dosificación , Tiempo de Trombina , Ticlopidina/administración & dosificación , Ticlopidina/farmacocinética , Adulto Joven
11.
Leuk Lymphoma ; 54(4): 708-13, 2013 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-22978685

RESUMEN

Polo-like kinase 1 (Plk1) is expressed during mitosis and overexpressed in multiple cancers, including non-Hodgkin lymphoma (NHL). This phase I study determined the maximum tolerated dose (MTD) of BI 2536, a Plk1 inhibitor, as a 1 h infusion once every 3 weeks in post-transplant relapsed (n = 17) and transplant-naive (n = 24) patients with relapsed/refractory NHL. Median treatment cycles were 2 and 1.5, respectively. MTD was 175 mg for both populations; dose-limiting toxicities were grade 4 thrombocytopenia and neutropenia. Most treatment-related adverse events were grade 1/2; drug-related grade 3/4 events included thrombocytopenia and neutropenia. Four patients achieved responses (three complete and one partial at doses ≥ 150 mg, all post-transplant relapsed patients) for an overall response rate of 9.8%. BI 2536 exhibited multi-compartmental pharmacokinetics with a high volume of distribution. The activity and safety of BI 2536 in this pretreated patient population support Plk inhibitors as a therapeutic strategy in oncology.


Asunto(s)
Linfoma no Hodgkin/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Pteridinas/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Proteínas de Ciclo Celular/antagonistas & inhibidores , Femenino , Humanos , Linfoma no Hodgkin/patología , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Proto-Oncogénicas/antagonistas & inhibidores , Pteridinas/farmacología , Resultado del Tratamiento , Adulto Joven , Quinasa Tipo Polo 1
12.
Eur J Cancer ; 48(2): 179-86, 2012 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-22119200

RESUMEN

BACKGROUND: Volasertib (BI 6727) is a potent and selective cell-cycle kinase inhibitor that induces mitotic arrest and apoptosis by targeting Polo-like kinase (Plk). This phase I dose-escalation study evaluated the maximum tolerated dose (MTD) of volasertib, safety and efficacy, and pharmacokinetic (PK) parameters. METHODS: This trial followed an open-label, toxicity-guided dose-titration design. Patients with progressive advanced or metastatic solid tumours received a single 1-h infusion of volasertib every 3 weeks. A total of 65 patients were treated at doses of 12-450 mg. RESULTS: Reversible haematological toxicity was the main side-effect; thrombocytopenia, neutropenia, and febrile neutropenia constituting the main dose-limiting events. Anaemia (all grades 22%; grade 3: 8%), neutropenia (15%; grade 3/4: 14%), fatigue (15%; grade 3: 2%), and thrombocytopenia (14%; grade 3/4: 14%) were the most frequent drug-related adverse events. The MTD was 400mg; however, 300 mg was the recommended dose for further development based on overall tolerability. Three patients achieved confirmed partial response. Stable disease as best response was reported in 40% of patients. Two patients remained progression free for >1 year. PK analysis showed no indication of deviation from 'dose-linear PK' behaviour, a large volume of distribution (>4000 l), moderate clearance and a long half-life (~111 h). CONCLUSION: This first-in-man trial demonstrated a favourable PK profile of volasertib, with manageable toxicities. As expected, the most common events were haematological. Encouraging preliminary antitumour activity has been observed, supporting Plk inhibition as a therapeutic approach. Clinical development of volasertib in phase II monotherapy and combination trials is ongoing.


Asunto(s)
Antineoplásicos/uso terapéutico , Neoplasias/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Pteridinas/uso terapéutico , Adulto , Anciano , Antineoplásicos/farmacocinética , Estudios de Cohortes , Relación Dosis-Respuesta a Droga , Femenino , Semivida , Humanos , Masculino , Persona de Mediana Edad , Neoplasias/metabolismo , Inhibidores de Proteínas Quinasas/farmacocinética , Pteridinas/farmacocinética , Adulto Joven
13.
Clin Cancer Res ; 16(18): 4666-74, 2010 Sep 15.
Artículo en Inglés | MEDLINE | ID: mdl-20682708

RESUMEN

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.


Asunto(s)
Proteínas de Ciclo Celular/antagonistas & inhibidores , Neoplasias/tratamiento farmacológico , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Proto-Oncogénicas/antagonistas & inhibidores , Pteridinas/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/efectos adversos , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapéutico , Progresión de la Enfermedad , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neoplasias/patología , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/farmacocinética , Inhibidores de Proteínas Quinasas/uso terapéutico , Pteridinas/efectos adversos , Pteridinas/farmacocinética , Resultado del Tratamiento , Quinasa Tipo Polo 1
14.
J Thorac Oncol ; 5(7): 1060-7, 2010 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-20526206

RESUMEN

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.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Proteínas de Ciclo Celular/antagonistas & inhibidores , Neoplasias Pulmonares/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Proto-Oncogénicas/antagonistas & inhibidores , Pteridinas/uso terapéutico , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/patología , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Pulmón de Células no Pequeñas/patología , Resistencia a Antineoplásicos , Femenino , Humanos , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/patología , Estadificación de Neoplasias , Neoplasias de Células Escamosas/tratamiento farmacológico , Neoplasias de Células Escamosas/patología , Terapia Recuperativa , Tasa de Supervivencia , Insuficiencia del Tratamiento , Resultado del Tratamiento , Quinasa Tipo Polo 1
15.
Eur J Cancer ; 46(12): 2206-15, 2010 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-20471824

RESUMEN

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.


Asunto(s)
Antineoplásicos/administración & dosificación , Neoplasias/tratamiento farmacológico , Pteridinas/administración & dosificación , Adulto , Anciano , Antineoplásicos/efectos adversos , Antineoplásicos/farmacocinética , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Estudios de Factibilidad , Femenino , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Neoplasias de Cabeza y Cuello/metabolismo , Humanos , Infusiones Intravenosas , Masculino , Melanoma/tratamiento farmacológico , Melanoma/metabolismo , Persona de Mediana Edad , Neoplasias/metabolismo , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/metabolismo , Cooperación del Paciente , Pteridinas/efectos adversos , Pteridinas/farmacocinética , Sarcoma/tratamiento farmacológico , Sarcoma/metabolismo , Resultado del Tratamiento , Adulto Joven
16.
Cancer Chemother Pharmacol ; 66(4): 785-95, 2010 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-20062994

RESUMEN

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.


Asunto(s)
Proteínas de Ciclo Celular/antagonistas & inhibidores , Neutropenia/inducido químicamente , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/farmacocinética , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Proto-Oncogénicas/antagonistas & inhibidores , Pteridinas/efectos adversos , Pteridinas/farmacocinética , Algoritmos , Cromatografía Líquida de Alta Presión , Interpretación Estadística de Datos , Semivida , Humanos , Recuento de Leucocitos , Espectrometría de Masas , Dosis Máxima Tolerada , Modelos Estadísticos , Neutropenia/epidemiología , Neutrófilos , Quinasa Tipo Polo 1
17.
Drug Metab Dispos ; 36(8): 1519-28, 2008 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-18458048

RESUMEN

The direct thrombin inhibitor melagatran is formed from ximelagatran via two intermediate metabolites, OH-melagatran and ethylmelagatran. The biotransformation of ximelagatran does not involve cytochrome P450 isoenzymes, and it has been suggested that a reported interaction with erythromycin may instead be mediated by transport proteins. A pig model that simultaneously enables bile collection, sampling from three blood vessels and perfusion of a jejunal segment, was used to investigate the biotransformation of ximelagatran and the effect of erythromycin on the intestinal and hepatobiliary transport of ximelagatran and its metabolites. The pigs received enteral ximelagatran (n = 6), enteral ximelagatran together with erythromycin (n = 6), i.v. ximelagatran (n = 4), or i.v. melagatran (n = 4). The plasma exposure of the intermediates was found to depend on the route of ximelagatran administration. Erythromycin increased the area under the plasma concentration-time curve (AUC) of melagatran by 45% and reduced its biliary clearance from 3.0 +/- 1.3 to 1.5 +/- 1.1 ml/min/kg. Extensive biliary exposure of melagatran and ethylmelagatran, mediated by active transport, was evident from the 100- and 1000-fold greater AUC, respectively, in bile than in plasma. Intestinal efflux transporters seemed to be of minor importance for the disposition of ximelagatran and its metabolites considering the high estimated f(abs) of ximelagatran (80 +/- 20%) and the negligible amount of the compounds excreted in the perfused intestinal segment. These findings suggest that transporters located at the sinusoidal and/or canalicular membranes of hepatocytes determine the hepatic disposition of ximelagatran and its metabolites, and are likely to mediate the ximelagatran-erythromycin pharmacokinetic interaction.


Asunto(s)
Anticoagulantes/farmacocinética , Azetidinas/farmacocinética , Bencilaminas/farmacocinética , Sistema Biliar/metabolismo , Mucosa Intestinal/metabolismo , Hígado/metabolismo , Animales , Anticoagulantes/administración & dosificación , Anticoagulantes/metabolismo , Área Bajo la Curva , Azetidinas/administración & dosificación , Azetidinas/metabolismo , Bencilaminas/administración & dosificación , Bencilaminas/metabolismo , Biotransformación , Porcinos
18.
Drug Metab Dispos ; 34(5): 775-82, 2006 May.
Artículo en Inglés | MEDLINE | ID: mdl-16455803

RESUMEN

A pharmacokinetic interaction between erythromycin and ximelagatran, an oral direct thrombin inhibitor, was demonstrated in this study in healthy volunteers. To investigate possible interaction mechanisms, the effects of erythromycin on active transport mediated by P-glycoprotein (P-gp) in vitro in Caco-2 and P-gp-over-expressing Madin-Darby canine kidney-human multidrug resistance-1 cell preparations and on biliary excretion of melagatran in rats were studied. In healthy volunteers (seven males and nine females; mean age 24 years) receiving a single dose of ximelagatran 36 mg on day 1, erythromycin 500 mg t.i.d. on days 2 to 5, and a single dose of ximelagatran 36 mg plus erythromycin 500 mg on day 6, the least-squares mean estimates (90% confidence intervals) for the ratio of ximelagatran with erythromycin to ximelagatran given alone were 1.82 (1.64-2.01) for the area under the concentration-time curve and 1.74 (1.52-2.00) for the maximum plasma concentration of melagatran, the active form of ximelagatran. Neither the slope nor the intercept of the melagatran plasma concentration-effect relationship for activated partial thromboplastin time statistically significantly differed as a function of whether or not erythromycin was administered with ximelagatran. Ximelagatran was well tolerated regardless of whether it was administered with erythromycin. Erythromycin inhibited P-gp-mediated transport of both ximelagatran and melagatran in vitro and decreased the biliary excretion of melagatran in the rat. These results indicate that the mechanism of the pharmacokinetic interaction between oral ximelagatran and erythromycin may involve inhibition of transport proteins, possibly P-gp, resulting in decreased melagatran biliary excretion and increased bioavailability of melagatran.


Asunto(s)
Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/antagonistas & inhibidores , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/fisiología , Antibacterianos/farmacología , Azetidinas/farmacocinética , Bencilaminas/farmacocinética , Eritromicina/farmacología , Adulto , Animales , Antibacterianos/efectos adversos , Antimaláricos/farmacología , Azetidinas/efectos adversos , Bencilaminas/efectos adversos , Bilis/metabolismo , Transporte Biológico Activo , Células CACO-2 , Bloqueadores de los Canales de Calcio/farmacología , Línea Celular , Perros , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Eritromicina/efectos adversos , Femenino , Humanos , Técnicas In Vitro , Masculino , Tiempo de Tromboplastina Parcial , Quinidina/farmacología , Ratas , Ratas Sprague-Dawley , Verapamilo/farmacología
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