RESUMO
BACKGROUND: Surgical resection is the only curative treatment option for gastric cancer. Despite widespread adoption of multimodality perioperative treatment strategies, 5-year overall survival rates remain low. In patients with advanced gastric or gastroesophageal junction adenocarcinoma, pembrolizumab has demonstrated promising efficacy and manageable safety as monotherapy in previously treated patients and as first-line therapy in combination with cisplatin and 5-fluorouracil. Combining chemotherapy with pembrolizumab in the neoadjuvant/adjuvant setting may benefit patients with locally advanced, resectable disease. AIM: To describe the design and rationale for the global, multicenter, randomized, double-blind, Phase III KEYNOTE-585 study to evaluate the efficacy and safety of pembrolizumab plus chemotherapy compared with placebo plus chemotherapy as neoadjuvant/adjuvant treatment for localized gastric or gastroesophageal junction adenocarcinoma. ClinicalTrials.gov : NCT03221426.
Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ensaios Clínicos Fase III como Assunto , Neoplasias Gástricas/terapia , Adulto , Quimioterapia Adjuvante/métodos , Intervalo Livre de Doença , Método Duplo-Cego , Feminino , Gastrectomia , Humanos , Masculino , Estudos Multicêntricos como Assunto , Terapia Neoadjuvante/métodos , Assistência Perioperatória/métodos , Ensaios Clínicos Controlados Aleatórios como Assunto , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/patologia , Análise de Sobrevida , Adulto JovemRESUMO
Vaniprevir is a competitive inhibitor of the hepatitis C virus (HCV) NS3/4A protease that has potent anti-HCV activity in preclinical models. This placebo-controlled dose-ranging study assessed the safety, tolerability, and antiviral efficacy of vaniprevir monotherapy in patients with genotype 1 chronic HCV infection. Treatment-naive and treatment-experienced non-cirrhotic adult patients with baseline HCV RNA >10(6)IU/ml were randomized to receive placebo or vaniprevir at doses of 125 mg qd, 600 mg qd, 25mg bid, 75 mg bid, 250 mg bid, 500 mg bid, and 700 mg bid for 8 days. Forty patients (82.5% male, 75% genotype 1a) received at least one dose of placebo or vaniprevir. After 1 week of vaniprevir, the decrease in HCV RNA from baseline ranged from 1.8 to 4.6 log10IU/ml across all treatment groups, and there was a greater than dose-proportional increase in vaniprevir exposure at doses above 75 mg bid. The most commonly reported drug-related adverse events (AEs) were diarrhea (n=5) and nausea (n=5). No pattern of laboratory or ECG abnormalities was observed, all AEs resolved during the study, and there were no discontinuations due to AEs. No serious AEs were reported. Resistance-associated amino acid variants were identified at positions R155 and D168 in patients infected with genotype 1a virus. Vaniprevir monotherapy demonstrated potent antiviral activity in patients with chronic genotype 1 HCV infection, and was generally well tolerated with no serious AEs or discontinuations due to AEs. Further development of vaniprevir, including studies in combination with other anti-HCV agents, is ongoing.
Assuntos
Antivirais/farmacocinética , Proteínas de Transporte/antagonistas & inibidores , Hepacivirus/efeitos dos fármacos , Hepatite C/tratamento farmacológico , Indóis/farmacocinética , Proteínas não Estruturais Virais/antagonistas & inibidores , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antivirais/efeitos adversos , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Ciclopropanos , Farmacorresistência Viral , Feminino , Genótipo , Hepacivirus/enzimologia , Hepacivirus/genética , Hepacivirus/isolamento & purificação , Hepatite C/virologia , Humanos , Indóis/efeitos adversos , Peptídeos e Proteínas de Sinalização Intracelular , Isoindóis , Lactamas Macrocíclicas , Leucina/análogos & derivados , Masculino , Pessoa de Meia-Idade , Prolina/análogos & derivados , Inibidores de Proteases/efeitos adversos , Inibidores de Proteases/farmacocinética , Sulfonamidas , Proteínas não Estruturais Virais/genética , Proteínas não Estruturais Virais/metabolismo , Adulto JovemRESUMO
This analysis is motivated by recent reviews on the carcinogenicity of beryllium by the International Agency for Research on Cancer, the U.S. Environmental Protection Agency, and the American Conference of Governmental Industrial Hygienists, and reconsideration by the National Toxicology Program on its classification of the carcinogenicity of beryllium. It reanalyzes data from a 1992 publication of a cohort mortality study conducted by the National Institute of Occupational Safety and Health (NIOSH) of workers employed in seven plants producing beryllium in the United States (Ward et al., 1992). That publication reported an increased risk of lung cancer in these workers and concluded that it is most likely due to occupational exposure to beryllium compounds. This present report uses: (1) an adjustment for smoking based on more germane estimates of the association between smoking and mortality from lung cancer; (2) computations of expected lung cancer rates based on alternative comparison populations; and (3) an overall combined estimate of the findings from the individual plants based on meta-analysis. Our findings indicate lower and generally not statistically significant standard mortality ratios that are not compatible with the interpretation of a likely causal association.
