Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 6 de 6
Filtrar
1.
Oncologist ; 28(6): 553-e472, 2023 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-36940261

RESUMO

BACKGROUND: The MORPHEUS platform comprises multiple open-label, randomized, phase Ib/II trials designed to identify early efficacy and safety signals of treatment combinations across cancers. Atezolizumab (anti-programmed cell death 1 ligand 1 [PD-L1]) was evaluated in combination with PEGylated recombinant human hyaluronidase (PEGPH20). METHODS: In 2 randomized MORPHEUS trials, eligible patients with advanced, previously treated pancreatic ductal adenocarcinoma (PDAC) or gastric cancer (GC) received atezolizumab plus PEGPH20, or control treatment (mFOLFOX6 or gemcitabine plus nab-paclitaxel [MORPHEUS-PDAC]; ramucirumab plus paclitaxel [MORPHEUS-GC]). Primary endpoints were objective response rates (ORR) per RECIST 1.1 and safety. RESULTS: In MORPHEUS-PDAC, ORRs with atezolizumab plus PEGPH20 (n = 66) were 6.1% (95% CI, 1.68%-14.80%) vs. 2.4% (95% CI, 0.06%-12.57%) with chemotherapy (n = 42). In the respective arms, 65.2% and 61.9% had grade 3/4 adverse events (AEs); 4.5% and 2.4% had grade 5 AEs. In MORPHEUS-GC, confirmed ORRs with atezolizumab plus PEGPH20 (n = 13) were 0% (95% CI, 0%-24.7%) vs. 16.7% (95% CI, 2.1%-48.4%) with control (n = 12). Grade 3/4 AEs occurred in 30.8% and 75.0% of patients, respectively; no grade 5 AEs occurred. CONCLUSION: Atezolizumab plus PEGPH20 showed limited clinical activity in patients with PDAC and none in patients with GC. The safety of atezolizumab plus PEGPH20 was consistent with each agent's known safety profile. (ClinicalTrials.gov Identifier: NCT03193190 and NCT03281369).


Assuntos
Adenocarcinoma , Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Neoplasias Gástricas , Humanos , Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma Ductal Pancreático/tratamento farmacológico , Hialuronoglucosaminidase/efeitos adversos , Paclitaxel/efeitos adversos , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/patologia , Neoplasias Gástricas/tratamento farmacológico
2.
Sci Transl Med ; 16(748): eadn0223, 2024 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-38753806

RESUMO

A protective HIV vaccine will likely need to induce broadly neutralizing antibodies (bnAbs). Vaccination with the germline-targeting immunogen eOD-GT8 60mer adjuvanted with AS01B was found to induce VRC01-class bnAb precursors in 97% of vaccine recipients in the IAVI G001 phase 1 clinical trial; however, heterologous boost immunizations with antigens more similar to the native glycoprotein will be required to induce bnAbs. Therefore, we designed core-g28v2 60mer, a nanoparticle immunogen to be used as a first boost after eOD-GT8 60mer priming. We found, using a humanized mouse model approximating human conditions of VRC01-class precursor B cell diversity, affinity, and frequency, that both protein- and mRNA-based heterologous prime-boost regimens induced VRC01-class antibodies that gained key mutations and bound to near-native HIV envelope trimers lacking the N276 glycan. We further showed that VRC01-class antibodies induced by mRNA-based regimens could neutralize pseudoviruses lacking the N276 glycan. These results demonstrated that heterologous boosting can drive maturation toward VRC01-class bnAb development and supported the initiation of the IAVI G002 phase 1 trial testing mRNA-encoded nanoparticle prime-boost regimens.


Assuntos
Vacinas contra a AIDS , Anticorpos Neutralizantes , Anticorpos Anti-HIV , Animais , Humanos , Vacinas contra a AIDS/imunologia , Anticorpos Neutralizantes/imunologia , Anticorpos Anti-HIV/imunologia , Camundongos , Vacinação , Imunização Secundária , HIV-1/imunologia , Infecções por HIV/imunologia , Infecções por HIV/prevenção & controle , Anticorpos Amplamente Neutralizantes/imunologia
3.
Commun Med (Lond) ; 2: 90, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35856081

RESUMO

Background: Treatment for metastatic colorectal cancer patients beyond the second line remains challenging, highlighting the need for early phase trials of combination therapies for patients who had disease progression during or following two prior lines of therapy. Leveraging hybrid control design in these trials may preserve the benefits of randomization while strengthening evidence by integrating historical trial data. Few examples have been established to assess the applicability of such design in supporting early phase metastatic colorectal cancer trials. Methods: MORPHEUS-CRC is an umbrella, multicenter, open-label, phase Ib/II, randomized, controlled trial (NCT03555149), with active experimental arms ongoing. Patients enrolled were assigned to a control arm (regorafenib, 15 patients randomized and 13 analysed) or multiple experimental arms for immunotherapy-based treatment combinations. One experimental arm (atezolizumab + isatuximab, 15 patients randomized and analysed) was completed and included in the hybrid-control study, where the hybrid-control arm was constructed by integrating data from the IMblaze370 phase 3 trial (NCT02788279). To estimate treatment efficacy, Cox and logistic regression models were used in a frequentist framework with standardized mortality ratio weighting or in a Bayesian framework with commensurate priors. The primary endpoint is objective response rate, while disease control rate, progression-free survival, and overall survival were the outcomes assessed in the hybrid-control study. Results: The experimental arm showed no efficacy signal, yet a well-tolerated safety profile in the MORPHEUS-CRC trial. Treatment effects estimated in hybrid control design were comparable to those in the MORPHEUS-CRC trial using either frequentist or Bayesian models. Conclusions: Hybrid control provides comparable treatment-effect estimates with generally improved precision, and thus can be of value to inform early-phase clinical development in metastatic colorectal cancer.

4.
Science ; 378(6623): eadd6502, 2022 12 02.
Artigo em Inglês | MEDLINE | ID: mdl-36454825

RESUMO

Broadly neutralizing antibodies (bnAbs) can protect against HIV infection but have not been induced by human vaccination. A key barrier to bnAb induction is vaccine priming of rare bnAb-precursor B cells. In a randomized, double-blind, placebo-controlled phase 1 clinical trial, the HIV vaccine-priming candidate eOD-GT8 60mer adjuvanted with AS01B had a favorable safety profile and induced VRC01-class bnAb precursors in 97% of vaccine recipients with median frequencies reaching 0.1% among immunoglobulin G B cells in blood. bnAb precursors shared properties with bnAbs and gained somatic hypermutation and affinity with the boost. The results establish clinical proof of concept for germline-targeting vaccine priming, support development of boosting regimens to induce bnAbs, and encourage application of the germline-targeting strategy to other targets in HIV and other pathogens.


Assuntos
Vacinas contra a AIDS , Anticorpos Amplamente Neutralizantes , Células Germinativas , Anticorpos Anti-HIV , Infecções por HIV , Cadeias Pesadas de Imunoglobulinas , Cadeias Leves de Imunoglobulina , Humanos , Adjuvantes Imunológicos , Vacinas contra a AIDS/imunologia , Anticorpos Amplamente Neutralizantes/genética , Anticorpos Amplamente Neutralizantes/imunologia , Infecções por HIV/prevenção & controle , Vacinação , Anticorpos Anti-HIV/genética , Anticorpos Anti-HIV/imunologia , Células Germinativas/imunologia , Linfócitos B/imunologia , Mutação , Cadeias Leves de Imunoglobulina/genética , Cadeias Leves de Imunoglobulina/imunologia , Cadeias Pesadas de Imunoglobulinas/genética , Cadeias Pesadas de Imunoglobulinas/imunologia , Masculino , Feminino , Adulto
5.
BMC Res Notes ; 10(1): 143, 2017 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-28376847

RESUMO

BACKGROUND: Variable selection is frequently carried out during the analysis of many types of high-dimensional data, including those in metabolomics. This study compared the predictive performance of four variable selection methods using stability-based selection, a new secondary selection method that is implemented in the R package BioMark. Two of these methods were evaluated using the more well-known false discovery rate (FDR) as well. RESULTS: Simulation studies varied factors relevant to biological data studies, with results based on the median values of 200 partial area under the receiver operating characteristic curve. There was no single top performing method across all factor settings, but the student t test based on stability selection or with FDR adjustment and the variable importance in projection (VIP) scores from partial least squares regression models obtained using a stability-based approach tended to perform well in most settings. Similar results were found with a real spiked-in metabolomics dataset. Group sample size, group effect size, number of significant variables and correlation structure were the most important factors whereas the percentage of significant variables was the least important. CONCLUSIONS: Researchers can improve prediction scores for their study data by choosing VIP scores based on stability variable selection over the other approaches when the number of variables is small to modest and by increasing the number of samples even moderately. When the number of variables is high and there is block correlation amongst the significant variables (i.e., true biomarkers), the FDR-adjusted student t test performed best. The R package BioMark is an easy-to-use open-source program for variable selection that had excellent performance characteristics for the purposes of this study.


Assuntos
Biomarcadores/análise , Simulação por Computador , Metabolômica/estatística & dados numéricos , Estatística como Assunto/métodos , Animais , Humanos , Análise dos Mínimos Quadrados , Modelos Teóricos , Análise Multivariada , Curva ROC , Reprodutibilidade dos Testes
6.
J Thorac Cardiovasc Surg ; 154(5): 1703-1710.e3, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28734628

RESUMO

OBJECTIVES: Adrenergic receptor (ADR) genotypes have been associated with adverse outcomes in heart failure. Our objective was to evaluate the association of ADR genotypes with post-Norwood outcomes in infants with hypoplastic left heart syndrome (HLHS). METHODS: Infants with HLHS participating in the Pediatric Heart Network Single-Ventricle Reconstruction Trial underwent genotyping for 4 single-nucleotide polymorphisms in 3 ADR genes: ADRB1_231A/G, ADRB1_1165G/C, ADRB2_5318C/G, and ADRA2A_2790C/T. The association of genotype with freedom from serious adverse events (SAEs) (death, transplant, extracorporeal membrane oxygenation, cardiopulmonary resuscitation, acute shunt failure, unplanned reoperations, or necrotizing enterocolitis) during 14 months' follow-up was assessed with Cox regression and the association with post-Norwood complications was assessed with Poisson regression. Models were adjusted for clinical and surgical factors. RESULTS: The study included 351 eligible patients (62% male; 83% white). The mean age at Norwood procedure was 5.6 ± 3.6 days. A total of 152 patients had SAEs during 14-month follow-up including 84 deaths and 10 transplants. ADRA2A_2790CC genotype had lower SAE-free survival compared with CT/TT genotypes during follow-up (Log rank test, P = .02), and this association was independent of clinical and surgical risk factors (adjusted Cox regression, hazard ratio 1.54 [95% confidence interval 1.04, 2.30] P = .033). Post-Norwood complication rate did not differ by genotype. CONCLUSIONS: Infants with HLHS harboring ADR genotypes that are associated with greater catecholamine release or sensitivity had lower event-free survival after staged palliation. Excess catecholamine activation may adversely affect cardiovascular adaptation after the Norwood procedure. Future studies should explore whether targeting adrenergic activation in those harboring risk genotypes can improve outcomes. (ClinicalTrials.gov number NCT00115934).


Assuntos
Síndrome do Coração Esquerdo Hipoplásico , Procedimentos de Norwood/efeitos adversos , Complicações Pós-Operatórias , Receptores Adrenérgicos alfa 2/genética , Receptores Adrenérgicos beta 1/genética , Receptores Adrenérgicos beta 2/genética , Correlação de Dados , Feminino , Seguimentos , Humanos , Síndrome do Coração Esquerdo Hipoplásico/genética , Síndrome do Coração Esquerdo Hipoplásico/cirurgia , Recém-Nascido , Masculino , Procedimentos de Norwood/métodos , Polimorfismo de Nucleotídeo Único , Complicações Pós-Operatórias/classificação , Complicações Pós-Operatórias/genética , Complicações Pós-Operatórias/terapia , Modelos de Riscos Proporcionais
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA