RESUMO
BACKGROUND: Rivoceranib is an oral, selective tyrosine kinase inhibitor of vascular endothelial growth factor receptor-2. ANGEL (NCT03042611) was a global, randomized, double-blinded, placebo-controlled, phase 3 study evaluating rivoceranib as 3rd-line or ≥4th-line therapy in patients with advanced/metastatic gastric or gastroesophageal junction (GEJ) cancer. METHODS: Patients had failed ≥2 lines of chemotherapy and were randomized 2:1 to rivoceranib 700 mg once daily or placebo with best supportive care. PRIMARY ENDPOINT: overall survival (OS) in the intention-to-treat population. Secondary endpoints: progression-free survival (PFS), objective response rate (ORR), and disease control rate (DCR) by blinded independent central review (BICR). RESULTS: In total, 460 patients (rivoceranib n = 308, placebo n = 152) were enrolled. OS was not statistically different for rivoceranib versus placebo (median 5.78 vs. 5.13 months; hazard ratio [HR] 0.93, 95% CI 0.74-1.15; p = 0.4724). PFS by BICR (median 2.83 vs. 1.77 months; HR 0.58, 95% CI 0.47-0.71; p < 0.0001), ORR (6.5% vs. 1.3%; p = 0.0119), and DCR (40.3 vs. 13.2%; p < 0.0001) were improved with rivoceranib versus placebo. In patients receiving ≥4th-line therapy, OS (median 6.34 vs. 4.73 months; p = 0.0192) and PFS by BICR (median 3.52 vs. 1.71 months; p < 0.0001) were improved with rivoceranib versus placebo. The most common grade ≥ 3 treatment-emergent adverse events with rivoceranib were hypertension (17.9%), anemia (10.4%), aspartate aminotransferase increased (9.4%), asthenia (8.5%), and proteinuria (7.5%). CONCLUSIONS: This study did not meet its primary OS endpoint. Compared to placebo, rivoceranib improved PFS, ORR, and DCR. Rivoceranib also improved OS in a prespecified patient subgroup receiving ≥4th-line therapy.
Assuntos
Piridinas , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/patologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular , Fator A de Crescimento do Endotélio Vascular , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Junção Esofagogástrica/patologia , Método Duplo-CegoRESUMO
PURPOSE: This study aimed to report the results from an early-phase study of rivoceranib, an oral tyrosine kinase inhibitor highly selective for vascular endothelial growth factor receptor 2, in patients with advanced solid tumors. MATERIALS AND METHODS: In this open-label, single-arm, dose-escalating, multicenter three-part phase 1/2a trial, patients had advanced solid tumors refractory to conventional therapy. Part 1 evaluated the safety and pharmacokinetics of five ascending once-daily doses of rivoceranib from 81 mg to 685 mg. Part 2 evaluated the safety and antitumor activity of once-daily rivoceranib 685 mg. Part 3 was conducted later, due to lack of maximum tolerated dose determination in part 1, to evaluate the safety and preliminary efficacy of once-daily rivoceranib 805 mg in patients with unresectable or advanced gastric cancer. RESULTS: A total of 61 patients were enrolled in parts 1 (n=25), 2 (n=30), and 3 (n=6). In parts 1 and 2, patients were white (45.5%) or Asian (54.5%), and 65.6% were male. The most common grade ≥ 3 adverse events were hypertension (32.7%), hyponatremia (10.9%), and hypophosphatemia (10.9%). The objective response rate (ORR) was 15.2%. In part 3, dose-limiting toxicities occurred in two out of six patients: grade 3 febrile neutropenia decreased appetite, and fatigue. The ORR was 33%. CONCLUSION: The recommended phase 2 dose of rivoceranib was determined to be 685 mg once daily, which showed adequate efficacy with a manageable safety profile (NCT01497704 and NCT02711969).
Assuntos
Inibidores da Angiogênese , Neoplasias , Receptor 2 de Fatores de Crescimento do Endotélio Vascular , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Adulto , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Inibidores da Angiogênese/uso terapêutico , Inibidores da Angiogênese/administração & dosagem , Inibidores da Angiogênese/efeitos adversos , Inibidores da Angiogênese/farmacocinética , Resultado do Tratamento , Dose Máxima Tolerável , Estadiamento de Neoplasias , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/farmacocinéticaRESUMO
Rivoceranib is a selective inhibitor of VEGFR-2 being developed for the treatment of solid tumor. The objective of the study was to evaluate the effect of food on bioavailability as well as single- and multiple-dose pharmacokinetics (PKs) of 81 and 201 mg doses of rivoceranib. The study was conducted as a two-part study. In Part 1 (single ascending dose (SAD), open-label, crossover study design), 2 oral doses of rivoceranib (81 mg or 201 mg) were given to all healthy subjects with a minimum 3-day washout period between dosing. Part 2 was a multiple ascending dose (MAD), open-label, crossover design where subjects were divided based on 81 and 201 mg doses. Both doses were administered with and without food in a crossover manner for the SAD and MAD parts. 24 healthy subjects completed Part 1 and 20 subjects completed Part 2. For the 81 mg dose in the SAD and MAD parts of the study, their food effect was not observed. For the 201 mg dose in both parts, food appeared to increase bioavailability by 20%-30% in Part 1, and 30%-40% in Part 2. Median tmax value was delayed when rivoceranib was administered with food at each dose level in both parts of the study. Dose proportionality was confirmed only for the AUC0-∞ value from Part 1-fasted cohort but inconclusive for Cmax and AUC parameters under other dosing regimens. In conclusion, rivoceranib when taken with food delays tmax appears to increase bioavailability at 201 mg dose.
Assuntos
Ingestão de Alimentos , Interações Alimento-Droga , Administração Oral , Área Sob a Curva , Estudos Cross-Over , Voluntários Saudáveis , Humanos , PiridinasRESUMO
Rivoceranib (known in China as apatinib) is a selective vascular endothelial growth factor receptor-2 (VEGFR-2) tyrosine kinase inhibitor which inhibits angiogenesis in solid tumors. The aim of study was to evaluate potential pharmacokinetic (PK) differences between the Caucasian, Japanese, and Chinese populations. An open-label, single-dose, parallel-design PK study of rivoceranib was conducted in Caucasian, Japanese, and Chinese subjects. A total of 18 healthy males were recruited to each group (54 total), and 201 mg rivoceranib tablets (as 250 mg rivoceranib mesylate) were administered orally to subjects. Plasma samples were collected, and rivoceranib plasma concentration was determined using LC-MS/MS. For PK analysis, non-compartmental and compartmental analyses were performed. Intrinsic factors (CYP2C19 and CYP3A4 genotype) were also examined. Non-compartmental analysis showed no significant difference in AUC0-t , AUC0-∞ , Cmax , tmax , and t1/2 . Apparent clearance and volume of distribution were different across the three populations; however, the extent of this difference does not require dose modification. For compartmental modeling, a two-compartment model was used to fit the plasma concentrations. No significant difference was observed in absorption, elimination, and intercompartmental transfer rate constants among the three groups. The present study shows no major ethnic PK differences between Caucasian, Japanese, and Chinese populations.
Assuntos
Antineoplásicos/farmacocinética , Piridinas/farmacocinética , Adulto , Antineoplásicos/administração & dosagem , Antineoplásicos/sangue , Área Sob a Curva , Povo Asiático , Humanos , Masculino , Pessoa de Meia-Idade , Piridinas/administração & dosagem , Piridinas/sangue , Estados Unidos , População Branca , Adulto JovemRESUMO
Considerable efforts have been made to exploit cardioprotective drugs and gene delivery systems for myocardial infarction (MI). The promising cardioprotective effects of recombinant human erythropoietin (rHuEPO) protein in animal experiments have not been consistently reproduced in clinical human trials of acute MI; however, the mechanisms underlying the inconsistent discrepancies are not yet fully understood. We hypothesized that the plasmid human erythropoietin gene (phEPO) delivered by our bioreducible polymer might produce cardioprotective effects on post-infarct cardiac remodeling. We demonstrated that intramyocardial delivery of phEPO by an arginine-grafted poly(disulfide amine) (ABP) polymer in infarcted rats preserves cardiac geometry and systolic function. The reduced infarct size of phEPO/ABP delivery was followed by decrease in fibrosis, protection from cardiomyocyte loss, and down-regulation of apoptotic activity. In addition, the increased angiogenesis and decreased myofibroblast density in the border zone of the infarct support the beneficial effects of phEPO/ABP administration. Furthermore, phEPO/ABP delivery induced prominent suppression on Ang II and TGF-ß activity in all subdivisions of cardiac tissues except for the central zone of infarct. These results of phEPO gene therapy delivered by a bioreducible ABP polymer provide insight into the lack of phEPO gene therapy translation in the treatment of acute MI to human trials.
Assuntos
Arginina/administração & dosagem , Cardiotônicos/administração & dosagem , Eritropoetina/genética , Infarto do Miocárdio/terapia , Poliaminas/administração & dosagem , Animais , Arginina/química , Cardiotônicos/química , Eritropoetina/química , Técnicas de Transferência de Genes , Masculino , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Miocárdio/metabolismo , Miocárdio/patologia , Poliaminas/química , Ratos , Ratos Sprague-Dawley , Remodelação VentricularRESUMO
Vascular endothelial growth factor (VEGF) gene therapy to promote therapeutic angiogenesis has been advanced as an alternative treatment for myocardial ischemia. The unregulated expression of VEGF and the use of viral vectors, however, have slowed the clinical development of angiogenic gene therapy. The development of clinically beneficial angiogenic gene therapy requires a disease-specific gene expression system and an efficient non-viral gene carrier. To address these requirements, we developed a new post-translationally regulated hypoxia-responsible VEGF plasmid, pß-SP-ODD-VEGF, and a dendrimer-type bio-reducible polymer, PAM-ABP. The efficacy of VEGF gene therapy with the PAM-ABP/pß-SP-ODD-VEGF was evaluated and compared to the RTP-VEGF plasmid, a previously constructed hypoxia-inducible plasmid, in an ischemia/reperfusion (I/R) rat model. Cine magnetic resonance imaging was used to analyze the ischemia/reperfusion rats treated with either the PAM-ABP/pß-SP-ODD-VEGF or the PAM-ABP/RTP-VEGF. The PAM-ABP/pß-SP-ODD-VEGF treatment more effectively protected cardiomyocytes against apoptosis, preserved left ventricular (LV) function, and prevented LV remodeling compared to the PAM-ABP/RTP-VEGF-treated rats. These results suggest that the pß-SP-ODD-VEGF with PAM-ABP may be efficacious in the treatment of acute ischemic heart disease.
Assuntos
Arginina/química , Dendrímeros/química , Isquemia Miocárdica/terapia , Plasmídeos/uso terapêutico , Poliaminas/química , Transfecção , Fator A de Crescimento do Endotélio Vascular/genética , Animais , Apoptose , Linhagem Celular , Expressão Gênica , Terapia Genética , Proteínas com Domínio LIM/análise , Proteínas com Domínio LIM/genética , Masculino , Isquemia Miocárdica/genética , Isquemia Miocárdica/patologia , Miocárdio/metabolismo , Miocárdio/patologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Plasmídeos/administração & dosagem , Plasmídeos/genética , Sinais Direcionadores de Proteínas , Ratos , Ratos Sprague-Dawley , Fator A de Crescimento do Endotélio Vascular/análiseRESUMO
Myocardial ischemia needs an alternative treatment such as gene therapy for the direct protection of cardiomyocytes against necrosis or apoptosis and to prevent the development of myocardial fibrosis and cardiac dysfunction. Despite the utility of gene therapy, its therapeutic use is limited due to inadequate transfection in cardiomyocytes and difficulty in directing to ischemic myocardium. Here, we present a polymeric gene carrier that is capable of targeting ischemic myocardium, resulting in high localization within the ischemic zone of the left ventricle (LV) of an ischemia/reperfusion (I/R) rat model upon systemic administration. Cystamine bisacrylamide-diamino hexane (CD) polymer was modified with the ischemic myocardium-targeted peptide (IMTP) and D-9-arginine (9R) for dual effects of the homing to ischemic myocardium and enhanced transfection efficiency with minimized polymer use. Conjugation of IMTP and 9R to CD led to an increase in transfection under hypoxia and significantly reduced the amount of polymer required for high transfection. Finally, we confirmed targeting of IMTP-CD-9R/DNA polyplex to ischemic myocardium and enhanced gene expression in LV of the I/R rat after tail vein injection. This study provides a clue that gene therapy for the treatment of myocardial ischemia can be achieved by using homing peptide-guided gene delivery systems.
Assuntos
Terapia Genética/métodos , Isquemia Miocárdica/genética , Isquemia Miocárdica/terapia , Peptídeos/administração & dosagem , Polímeros/administração & dosagem , Animais , Células Cultivadas , DNA/administração & dosagem , DNA/genética , Portadores de Fármacos/administração & dosagem , Expressão Gênica/genética , Técnicas de Transferência de Genes , Ventrículos do Coração/efeitos dos fármacos , Ventrículos do Coração/metabolismo , Hipóxia/tratamento farmacológico , Hipóxia/genética , Masculino , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Peptídeos/genética , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/genética , Transfecção/métodosRESUMO
Feeding tube placement for enteral nutrition (EN) support is widely used in both critically ill and stable chronically ill patients who are unable to meet their nutrition needs orally. Nasal or oral feeding tubes can be performed blindly at the bedside or with fluoroscopic or endoscopic guidance into the stomach or small bowel. Percutaneous feeding tubes are used when EN support is required for longer periods (>4-6 weeks) and are most commonly placed endoscopically or radiographically. Although generally safe and effective, there is a wide spectrum of known complications associated with feeding tube placement. Errors made at the time of feeding tube placement can result in a number of these procedural and postprocedural complications. In many cases, a single error at the time of placement can result in numerous complications. A thorough knowledge of these errors and avoiding them in practice will decrease iatrogenic complications in a vulnerable population. In addition, early recognition and management of complications will further minimize morbidity and even mortality in enteral feeding tube placement. This article reviews the common errors leading to complications of enteral feeding tube placement and their prevention and management.
Assuntos
Nutrição Enteral/instrumentação , Gastrostomia/métodos , Intubação Gastrointestinal/efeitos adversos , Intubação Gastrointestinal/métodos , Administração Cutânea , Estado Terminal/terapia , Endoscopia/métodos , Fluoroscopia/métodos , Mucosa Gástrica/metabolismo , Humanos , Intestino Delgado/metabolismoRESUMO
Implantation of skeletal myoblasts to the heart has been investigated as a means to regenerate and protect the myocardium from damage after myocardial infarction. While several animal studies utilizing skeletal myoblasts have reported positive findings, results from clinical studies have been mixed. In this study we utilize a newly developed bioreducible polymer system to transfect skeletal myoblasts with a plasmid encoding vascular endothelial growth factor (VEGF) prior to implantation into acutely ischemic myocardium. VEGF has been demonstrated to promote revascularization of the myocardium following myocardial infarction. We report that implanting VEGF expressing skeletal myoblasts into acutely ischemic myocardium produces superior results compared to implantation of untransfected skeletal myoblasts. Skeletal myoblasts expressing secreted VEGF were able to restore cardiac function to non-diseased levels as measured by ejection fraction, to limit remodeling of the heart chamber as measured by end systolic and diastolic volumes, and to prevent myocardial wall thinning. Additionally, arteriole and capillary formation, retention of viable cardiomyocytes, and prevention of apoptosis was significantly improved by VEGF expressing skeletal myoblasts compared to untransfected myoblasts. This work demonstrates the feasibility of using bioreducible cationic polymers to create engineered skeletal myoblasts to treat acutely ischemic myocardium.
Assuntos
Materiais Biocompatíveis/química , Mioblastos Esqueléticos/metabolismo , Isquemia Miocárdica/terapia , Polímeros/química , Transfecção/métodos , Fator A de Crescimento do Endotélio Vascular/genética , Animais , Células Cultivadas , Terapia Genética/métodos , Imuno-Histoquímica , Imageamento por Ressonância Magnética , Masculino , Ratos , Ratos Sprague-Dawley , Fator A de Crescimento do Endotélio Vascular/fisiologiaRESUMO
A cardiomyocyte-targeted Fas siRNA delivery system was developed using primary cardiomyocyte (PCM) specific peptide-modified polymers with high transfection efficiency and low cytotoxicity. Primary cardiomyocyte (PCM) specific peptide, selected by phage display, was conjugated to bioreducible poly(cystamine bisacrylamide-diaminohexane, CBA-DAH) (PCD). The specificity of the PCM-modified polymer to cardiomyocytes was confirmed by competition study with free PCM ligand and by delivery to non-cardiomyocyte NIH 3T3 fibroblasts. The cellular binding and uptake of the PCM-polymer/pDNA polyplex was inhibited by addition of free PCM peptide. The impact of PCM conjugation on cellular uptake and transfection efficiency was greater in H9C2 rat cardiomyocytes than in NIH 3T3 cells. Fas siRNA/PCM-polymer polyplexes exhibited significant Fas gene silencing in rat cardiomyocytes under hypoxic conditions, leading to inhibition of cardiomyocyte apoptosis. These findings demonstrate the utility of the addition of a primary cardiomyocyte (PCM) specific peptide modification to a bioreducible polymer for targeted delivery of Fas siRNA to inhibit cardiomyocyte apoptosis.
Assuntos
Materiais Biocompatíveis/farmacologia , Técnicas de Transferência de Genes , Miocárdio/metabolismo , Miócitos Cardíacos/metabolismo , Polímeros/farmacologia , Animais , Apoptose/efeitos dos fármacos , Células Cultivadas , Citometria de Fluxo , Inativação Gênica/efeitos dos fármacos , Camundongos , Miocárdio/citologia , Miócitos Cardíacos/citologia , Miócitos Cardíacos/efeitos dos fármacos , Células NIH 3T3 , Peptídeos/farmacologia , RNA Interferente Pequeno/metabolismo , Ratos , Transfecção , Receptor fas/metabolismoRESUMO
It is difficult to quantify NH4+ by ion chromatography in the presence of high concentrations of Na+ due to peak overlap. The Dionex IonPac CS15 column, which contains phosphonate, carboxylate, and 18-crown-6 functional groups, was originally developed to overcome this problem. We have found that the addition of 18-crown-6 to the eluent promotes improved peak resolution between Na+ and NH4+ even at concentrations as high as 60,000 to 1 using this column. Its use also improves the separation of alkali and alkaline earth metal and amine cations. Mobile phase 18-crown-6 increased the retention times of CH3NH3+, NH4+, and K+, and decreased the retention time of Sr2+. The retention times of Li+, Na+, Mg2+, Ca2+, (CH3)2NH2+, and (CH3)3NH+ were not affected. This method makes possible the direct analysis of ammonia from nitrogenase, the enzyme responsible for biological nitrogen fixation. The resolution of the NH4+ peak from the Na+ and Mg2+ peaks improved from zero resolution to values of 6.19 and 5.65, respectively. This technique considerably reduces the analysis time of NH4+ in the presence of high concentrations of Mg2+ and Na+ over traditional indophenol measurements.