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1.
Ann Oncol ; 29(8): 1807-1813, 2018 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-29992241

RESUMO

Background: Patients with castration-resistant prostate cancer derive only modest clinical benefit from available therapies. Blockade of the inhibitory programmed death 1 (PD-1) receptor by monoclonal antibodies has been effective in several malignancies. Results from the prostate adenocarcinoma cohort of the nonrandomized phase Ib KEYNOTE-028 trial of pembrolizumab in advanced solid tumors are presented. Materials and methods: Key eligibility criteria included advanced prostate adenocarcinoma, unsuccessful standard therapy, measurable disease per Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1), and PD-1 ligand (PD-L1) expression in ≥1% of tumor or stromal cells. Patients received pembrolizumab 10 mg/kg every 2 weeks until disease progression or intolerable toxicity for up to 24 months. Primary end point was objective response rate (ORR) per RECIST v1.1 by investigator review. Results: Median patient age in this cohort (n = 23) was 65 years; 73.9% of patients received at least two prior therapies for metastatic disease. There were four confirmed partial responses, for an ORR of 17.4% [95% confidence interval (CI) 5.0%-38.8%]; 8 of 23 (34.8%) patients had stable disease. Median duration of response was 13.5 months. Median progression-free survival (PFS) and overall survival (OS) were 3.5 and 7.9 months, respectively; 6-month PFS and OS rates were 34.8% and 73.4%, respectively. One patient remained on treatment at data cutoff. After a median follow-up of 7.9 months, 14 (60.9%) patients experienced treatment-related adverse events (TRAEs), most commonly nausea (n = 3, 13.0%). Four (17.3%) experienced grade 3/4 TRAEs: grade 3 peripheral neuropathy, grade 3 asthenia, grade 3 fatigue, and grade 4 lipase increase. No pembrolizumab-related deaths or discontinuations occurred. Conclusion: Pembrolizumab resulted in durable objective response in a subset of patients with heavily pretreated, advanced PD-L1-positive prostate cancer, and its side effect profile was favorable. ClinicalTrials.gov Identifier: NCT02054806.


Assuntos
Adenocarcinoma/tratamento farmacológico , Anticorpos Monoclonais Humanizados/administração & dosagem , Antineoplásicos Imunológicos/administração & dosagem , Neoplasias da Próstata/tratamento farmacológico , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/efeitos adversos , Antineoplásicos Imunológicos/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Náusea/induzido quimicamente , Náusea/epidemiologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Intervalo Livre de Progressão , Próstata/patologia , Neoplasias da Próstata/mortalidade , Neoplasias da Próstata/patologia , Critérios de Avaliação de Resposta em Tumores Sólidos
2.
Ann Oncol ; 28(5): 1036-1041, 2017 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-28453692

RESUMO

Background: Safety and efficacy of pembrolizumab, a humanized programmed death 1 monoclonal antibody, was assessed in KEYNOTE-028, a multicohort, phase Ib trial for patients with programmed death ligand 1 (PD-L1)-positive advanced solid tumors. We report results for the cohort of patients with advanced anal carcinoma. Patients and methods: Patients with PD-L1-positive tumors (≥1%) received intravenous pembrolizumab 10 mg/kg once every 2 weeks for up to 2 years or until confirmed progression or unacceptable toxicity. Response was assessed every 8 weeks for the first 6 months and every 12 weeks thereafter per Response Evaluation Criteria In Solid Tumors, version 1.1. Primary endpoints were safety and overall response rate per investigator review. Secondary endpoints included progression-free survival, overall survival, and response duration. Data cutoff date was 1 July 2015. Results: Of the 43 patients with advanced anal carcinoma evaluable for PD-L1 expression, 32 (74%) had PD-L1-positive tumors as assessed with the 22C3 prototype assay, of whom 25 were enrolled between April and September 2014. Sixteen patients (64%) experienced treatment-related adverse events; the most common ones were diarrhea and fatigue in four patients (16%) each and nausea in three patients (12%). There were no treatment-related deaths or discontinuations as of the data cutoff date. Among the 24 patients with squamous cell carcinoma histology, four had confirmed partial response, for an overall response rate of 17% [95% confidence interval (CI), 5%-37%) and 10 (42%) had confirmed stable disease, for a disease control rate of 58%. One additional patient with non-squamous histology had confirmed stable disease. Conclusion: In this population of patients with PD-L1-positive advanced squamous cell anal carcinoma, pembrolizumab demonstrated a manageable safety profile and encouraging antitumor activity. These data support further study of pembrolizumab for this patient population. ClinicalTrials.gov: NCT02054806.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Neoplasias do Ânus/tratamento farmacológico , Carcinoma de Células Escamosas/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Canal Anal/patologia , Anticorpos Monoclonais Humanizados/efeitos adversos , Antineoplásicos Imunológicos/efeitos adversos , Neoplasias do Ânus/mortalidade , Carcinoma de Células Escamosas/mortalidade , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/mortalidade , Resultado do Tratamento
3.
Ann Oncol ; 27(10): 1928-40, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27672108

RESUMO

BACKGROUND: To evaluate the safety, tolerability, pharmacokinetics, and maximum tolerated dose (MTD) of copanlisib, a phosphatidylinositol 3-kinase inhibitor, in patients with advanced solid tumors or non-Hodgkin's lymphoma (NHL). PATIENTS AND METHODS: Phase I dose-escalation study including patients with advanced solid tumors or NHL, and a cohort of patients with type 2 diabetes mellitus. Patients received three weekly intravenous infusions of copanlisib per 28-day cycle over the dose range 0.1-1.2 mg/kg. Plasma copanlisib levels were analyzed for pharmacokinetics. Biomarker analysis included PIK3CA, KRAS, BRAF, and PTEN mutational status and PTEN immunohistochemistry. Whole-body [(18)F]-fluorodeoxyglucose positron emission tomography ((18)FDG-PET) was carried out at baseline and following the first dose to assess early pharmacodynamic effects. Plasma glucose and insulin levels were evaluated serially. RESULTS: Fifty-seven patients received treatment. The MTD was 0.8 mg/kg copanlisib. The most frequent treatment-related adverse events were nausea and transient hyperglycemia. Copanlisib exposure was dose-proportional with no accumulation; peak exposure positively correlated with transient hyperglycemia post-infusion. Sixteen of 20 patients treated at the MTD had reduced (18)FDG-PET uptake; 7 (33%) had a reduction >25%. One patient achieved a complete response (CR; endometrial carcinoma exhibiting both PIK3CA and PTEN mutations and complete PTEN loss) and two had a partial response (PR; both metastatic breast cancer). Among the nine NHL patients, all six with follicular lymphoma (FL) responded (one CR and five PRs) and one patient with diffuse large B-cell lymphoma had a PR by investigator assessment; two patients with FL who achieved CR (per post hoc independent radiologic review) were on treatment >3 years. CONCLUSION: Copanlisib, dosed intermittently on days 1, 8, and 15 of a 28-day cycle, was well tolerated and the MTD was determined to be 0.8 mg/kg. Copanlisib exhibited dose-proportional pharmacokinetics and promising anti-tumor activity, particularly in patients with NHL. CLINICALTRIALSGOV: NCT00962611; https://clinicaltrials.gov/ct2/show/NCT00962611.


Assuntos
Classe I de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Inibidores Enzimáticos/administração & dosagem , Linfoma não Hodgkin/tratamento farmacológico , Neoplasias/tratamento farmacológico , Pirimidinas/administração & dosagem , Quinazolinas/administração & dosagem , Administração Intravenosa , Adulto , Idoso , Classe I de Fosfatidilinositol 3-Quinases/genética , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/efeitos adversos , Inibidores Enzimáticos/farmacocinética , Feminino , Humanos , Linfoma não Hodgkin/enzimologia , Linfoma não Hodgkin/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias/enzimologia , Neoplasias/patologia , Pirimidinas/efeitos adversos , Pirimidinas/farmacocinética , Quinazolinas/efeitos adversos , Quinazolinas/farmacocinética
5.
Carcinogenesis ; 10(5): 823-6, 1989 May.
Artigo em Inglês | MEDLINE | ID: mdl-2539914

RESUMO

Supplementation with increasing quantities of selenium (Se), as sodium selenite, to cultures of rat mammary epithelial cells resulted in a proportional depression in 7,12-dimethylbenz[a]anthracene (DMBA) binding to DNA. A depression in the two major anti bay-region dihydrodiol epoxide-deoxyribonucleoside adducts largely accounted for the reduced binding. DMBA-DNA binding in freshly isolated mammary cells from rats fed a diet containing 2.0 p.p.m. Se and incubated in culture with DMBA for 24 h was decreased 32% compared to binding in cells obtained from rats fed 0.1 p.p.m. Se. DMBA-DNA binding in mammary cells obtained from rats fed supplemental Se for 2 weeks or more was depressed compared to that occurring in cells from unsupplemented rats. The reduced ability of cells obtained from rats previously fed a 2.0 p.p.m. Se diet to activate DMBA to intermediates capable of binding to DNA became increasingly apparent with the duration of exposure to the carcinogen. Consistent with the in vitro supplementation study, cells isolated from rats previously fed a diet containing 2.0 p.p.m. Se had a reduced occurrence of the two major anti dihydrodiol epoxide adducts. The depression in DMBA binding following selenite supplementation, both in vitro and in vivo, supports the ability of Se to inhibit the initiation phase of carcinogenesis.


Assuntos
9,10-Dimetil-1,2-benzantraceno/análogos & derivados , Adutos de DNA , DNA/metabolismo , Glândulas Mamárias Animais/metabolismo , Selênio/farmacologia , 9,10-Dimetil-1,2-benzantraceno/metabolismo , Animais , Dieta , Epitélio/efeitos dos fármacos , Epitélio/metabolismo , Feminino , Técnicas In Vitro , Cinética , Glândulas Mamárias Animais/efeitos dos fármacos , Ratos , Ratos Endogâmicos , Valores de Referência , Selênio/administração & dosagem , Selenito de Sódio
6.
Biochemistry ; 27(1): 472-81, 1988 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-2831961

RESUMO

The mutagenic and carcinogenic chemical aflatoxin B1 (AFB1) reacts almost exclusively at the N(7)-position of guanine following activation to its reactive form, the 8,9-epoxide (AFB1 oxide). In general N(7)-guanine adducts yield DNA strand breaks when heated in base, a property that serves as the basis for the Maxam-Gilbert DNA sequencing reaction specific for guanine. Using DNA sequencing methods, other workers have shown that AFB1 oxide gives strand breaks at positions of guanines; however, the guanine bands varied in intensity. This phenomenon has been used to infer that AFB1 oxide prefers to react with guanines in some sequence contexts more than in others and has been referred to as "sequence specificity of binding". Herein, data on the reaction of AFB1 oxide with several synthetic DNA polymers with different sequences are presented, and (following hydrolysis) adduct levels are determined by high-pressure liquid chromatography. These results reveal that for AFB1 oxide (1) the N(7)-guanine adduct is the major adduct found in all of the DNA polymers, (2) adduct levels vary in different sequences, and, thus, sequence specificity is also observed by this more direct method, and (3) the intensity of bands in DNA sequencing gels is likely to reflect adduct levels formed at the N(7)-position of guanine. Knowing this, a reinvestigation of the reactivity of guanines in different DNA sequences using DNA sequencing methods was undertaken. The reactivities of 190 guanines were determined quantitatively and considered in a pentanucleotide context, 5'-WXGYZ-3', where the central, underlined G represents the reactive guanine and W, X, Y, and Z can be any of the nucleotide bases. Methods are developed to determine that the X (5'-side) base and the Y (3'-side) base are most influential in determining guanine reactivity. The influence of the bases in the 5'-position (X) is 5'-G (1.0) greater than C (0.8) greater than A (0.3) greater than T (0.2), while the influence of the bases in the 3'-position (Y) is 3'-G (1.0) greater than T (0.8) greater than C (0.4) greater than A (0.3). These rules in conjunction with molecular modeling studies (to be published elsewhere) were used to assess the binding sites that might be utilized by AFB1 oxide in its reaction with DNA.


Assuntos
Aflatoxinas/metabolismo , DNA/metabolismo , Guanina , Polidesoxirribonucleotídeos/metabolismo , Aflatoxina B1 , Sequência de Bases , Enzimas de Restrição do DNA , Ligação Proteica , Relação Estrutura-Atividade
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