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1.
Clin Cancer Res ; 27(10): 2723-2733, 2021 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-33622704

RESUMO

PURPOSE: BAY1436032, an inhibitor of mutant isocitrate dehydrogenase 1 (mIDH1), was active against multiple IDH1-R132X solid tumors in preclinical models. This first-in-human study was designed to determine the safety and pharmacokinetics of BAY1436032, and to evaluate its potential pharmacodynamics and antitumor effects. PATIENTS AND METHODS: The study comprised of dose escalation and dose expansion cohorts. BAY1436032 tablets were orally administered twice daily on a continuous basis in subjects with mIDH1 solid tumors. RESULTS: In dose escalation, 29 subjects with various tumor types were administered BAY1436032 across five doses (150-1,500 mg twice daily). BAY1432032 exhibited a relatively short half-life. Most evaluable subjects experienced target inhibition as indicated by a median maximal reduction of plasma R-2-hydroxyglutarate levels of 76%. BAY1436032 was well tolerated and an MTD was not identified. A dose of 1,500 mg twice daily was selected for dose expansion, where 52 subjects were treated in cohorts representing four different tumor types [lower grade glioma (LGG), glioblastoma, intrahepatic cholangiocarcinoma, and a basket cohort of other tumor types]. The best clinical outcomes were in subjects with LGG (n = 35), with an objective response rate of 11% (one complete response and three partial responses) and stable disease in 43%. As of August 2020, four of these subjects were in treatment for >2 years and still ongoing. Objective responses were observed only in LGG. CONCLUSIONS: BAY1436032 was well tolerated and showed evidence of target inhibition and durable objective responses in a small subset of subjects with LGG.


Assuntos
Compostos de Anilina/uso terapêutico , Antineoplásicos/uso terapêutico , Benzimidazóis/uso terapêutico , Isocitrato Desidrogenase/antagonistas & inibidores , Isocitrato Desidrogenase/genética , Mutação , Neoplasias/tratamento farmacológico , Neoplasias/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Compostos de Anilina/administração & dosagem , Compostos de Anilina/efeitos adversos , Compostos de Anilina/farmacocinética , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Benzimidazóis/administração & dosagem , Benzimidazóis/efeitos adversos , Benzimidazóis/farmacocinética , Biomarcadores Tumorais , Análise Mutacional de DNA , Gerenciamento Clínico , Suscetibilidade a Doenças , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Neoplasias/diagnóstico , Neoplasias/mortalidade
2.
J Urol ; 182(4 Suppl): 1978-83, 2009 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-19695589

RESUMO

PURPOSE: We determined the prevalence of lower urinary tract symptoms in enuretic and nonenuretic children and adolescents in an urban community. MATERIAL AND METHODS: We performed a cross-sectional survey including 296 children and adolescents in a small urban community. Trained medical students visited all homes and interviewed the parents or guardians. There were no refusals to participate. Results were analyzed using chi-square and McNemar statistics. RESULTS: The enuresis rate was 10%, including 16.6% and 3.9% in children 5 to 10 years old and adolescents, respectively. The monosymptomatic enuresis rate was only 1.34%. Of those with vs without enuresis lower urinary tract symptoms were present in 86.7% vs 26.8% (p <0.001). In the nonenuretic group lower urinary tract symptoms were associated with nocturia (p = 0.008). The most common daytime urinary symptoms were urgency in 38.2% of cases, holding maneuvers in 30.4% and daytime incontinence in 27.5%. The prevalence rate decreased with age in the nonenuretic group (p = 0.013). CONCLUSIONS: The prevalence of lower urinary tract symptoms was high. Nonmonosymptomatic enuresis was common and monosymptomatic enuresis was rare in this population based survey. In nonenuretic cases daytime symptoms were associated with nocturia, suggesting decreased bladder capacity with a mature arousal reaction.


Assuntos
Enurese/complicações , Transtornos Urinários/epidemiologia , Transtornos Urinários/etiologia , Adolescente , Criança , Pré-Escolar , Estudos Transversais , Feminino , Humanos , Masculino , Prevalência
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