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1.
Gan To Kagaku Ryoho ; 48(10): 1269-1271, 2021 Oct.
Artigo em Japonês | MEDLINE | ID: mdl-34657061

RESUMO

In 2 patients with postoperative lung metastases from renal cell carcinoma, we administered cabozantinib at a starting dose of 40 mg. The side effects were proteinuria(Grade 2), hand-foot syndrome(Grade 2), and hypertension(Grade 3), which subsided following dose reduction and drug suspension. We believe that a low starting dose of cabozantinib might be a suitable regimen for advanced renal cell carcinoma.


Assuntos
Antineoplásicos , Carcinoma de Células Renais , Neoplasias Renais , Anilidas/efeitos adversos , Antineoplásicos/efeitos adversos , Carcinoma de Células Renais/tratamento farmacológico , Humanos , Neoplasias Renais/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Piridinas/efeitos adversos
2.
Ann Palliat Med ; 10(9): 9902-9913, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34551570

RESUMO

BACKGROUND: Apatinib in combination with chemotherapy (CT) has been used in the treatment of ovarian cancer (OC), however, the safety and efficacy are unclear. The study aims at systematic evaluation of the safety and efficacy of the apatinib targeted therapy in combination with CT for the treatment of patients with advanced OC. METHODS: Literature about randomized controlled clinical trials was searched using search engines such as PubMed, EMBASE, Web of Science, CNKI, the Cochrane Library, CBM, VIP and the Wanfang. We collected the related clinical studies of apatinib in combination with CT in the treatment of OC. The duration of the data retrieval related to clinical studies was from the database establishment to September 2020. Adverse reactions (ADRs) due to treatment, disease control rate (DCR), and that of objective response rate (ORR), were collected as indicators to show treatment outcomes. The literature was independently screened by two researchers. They extracted the data and evaluated the risk of biases of the included studies. Then, Revman 5.4 software was employed for performing the meta-analysis. RESULTS: Twelve randomized controlled clinical trials with 698 patients having an advanced stage of OC were included. The results revealed that in comparison with the treatment with only CT, apatinib targeted therapy combination with CT showed significant improvement in the patients' ORR [OR =3.19, 95% CI: (2.06, 4.94), P<0.00001] and DCR [OR =4.97, 95% CI: (2.90, 8.52), P<0.00001]. The group that was treated with a combined therapy had shown proteinuria in higher amount (OR =3.08, 95% CI: 51.13-8.42, P<0.00001), while the analyses of other ADRs, such nausea and vomiting (OR =1.10, 95% CI: 0.67-1.79, P=0.71), hand-foot syndrome (OR =1.73, 95% CI: 0.97-3.10, P=0.06), hypertension (OR =1.18, 95% CI: 0.73-1.91, P=0.0.51), diarrhea (OR =1.05, 95% CI: 0.56-1.97, P=0.87), leucopenia (OR =1.22, 95% CI: 0.70-2.12, P=0.48), and myelosuppression (OR =1.00, 95% CI: 0.28-3.62, P=1.00), did not show any significant difference (P>0.05). DISCUSSION: The effects of apatinib combination with CT for the treatment of OC are significantly better than the CT used alone in ORR and DCR, despite with a relative low incidence of adverse effects. However, due to the very low number of studies available, the results need to be further verified using a high-quality, large sample and long-term studies.


Assuntos
Neoplasias Ovarianas , Piridinas , Feminino , Humanos , Neoplasias Ovarianas/tratamento farmacológico , Piridinas/efeitos adversos , Resultado do Tratamento
3.
BMC Cancer ; 21(1): 1054, 2021 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-34563169

RESUMO

BACKGROUND: Cervical cancer is the tenth diagnosed cancer in the world. Early-stage and locally recurrent disease may be cured with radical surgery or chemo-radiotherapy. However, if disease persists or recurs, options are limited and the prognosis is poor. In addition to chemotherapy, bevacizumab, an antiangiogenic agent, has recently demonstrated its efficacy in this setting. Cabozantinib is an oral small molecule tyrosine kinase inhibitor that exhibits potent inhibitory activity against several receptor tyrosine kinases that are known to influence tumor growth, metastasis, and angiogenesis. The main targets of Cabozantinib are VEGFR2, MET and AXL. It is currently approved for the treatment of metastatic renal cell carcinoma, hepatocellular carcinoma and medullary thyroid carcinoma. Given its angiogenic properties associated with growth factor receptors inhibition, Cabozantinib represents a potential active treatment in cervical carcinoma. In this context, we propose to assess the efficacy and safety of cabozantinib monotherapy in advanced/metastatic cervical carcinoma (CC) after failure to platinum-based regimen treatment. METHODS: This study is a single-arm two-stage multicenter phase II aiming to simultaneously assess efficacy and safety of Cabozantinib among advanced/metastatic cervical carcinoma (CC) after failure to platinum-based regimen treatment. The main criterion will be based on both safety and clinical efficacy by conducting a Bryant-and-Day design. Safety endpoint is the proportion of patients with clinical gastro-intestinal (GI) perforation/fistula, GI-vaginal fistula and genito-urinary (GU) fistula events grade ≥ 2 (NCI CTCAE V.5.0) occurring up to one month after the end of treatment. Efficacy endpoint is the proportion of patients with disease control rate 3 months after Cabozantinib initiation. A patients' self-reported quality of life evaluation is also planned, as well as the investigation of nutritional outcomes. Cabozantinib will be administered at the daily dose of 60 mg given orally, without interruption until disease progression or discontinuation for any cause. DISCUSSION: Cabozantinib is a promising drug for patients with advanced/metastatic cervical cancer where few therapeutics options are available after failure to platinum-based regimen metastatic CC. It appears challenging to assess the interest of Cabozantinib in this indication, taking into account the potential toxicity of the drug. TRIAL REGISTRATION: NCT04205799 , registered "2019 12 19". PROTOCOL VERSION: Version 3.1 dated from 2020 08 31.


Assuntos
Anilidas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Piridinas/uso terapêutico , Neoplasias do Colo do Útero/tratamento farmacológico , Adulto , Anilidas/efeitos adversos , Feminino , Humanos , Compostos de Platina/uso terapêutico , Inibidores de Proteínas Quinases/efeitos adversos , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Piridinas/efeitos adversos , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Falha de Tratamento , Neoplasias do Colo do Útero/patologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores
4.
N Engl J Med ; 385(9): 815-825, 2021 08 26.
Artigo em Inglês | MEDLINE | ID: mdl-34437784

RESUMO

BACKGROUND: Elexacaftor-tezacaftor-ivacaftor is a small-molecule cystic fibrosis transmembrane conductance regulator (CFTR) modulator regimen shown to be efficacious in patients with at least one Phe508del allele, which indicates that this combination can modulate a single Phe508del allele. In patients whose other CFTR allele contains a gating or residual function mutation that is already effectively treated with previous CFTR modulators (ivacaftor or tezacaftor-ivacaftor), the potential for additional benefit from restoring Phe508del CFTR protein function is unclear. METHODS: We conducted a phase 3, double-blind, randomized, active-controlled trial involving patients 12 years of age or older with cystic fibrosis and Phe508del-gating or Phe508del-residual function genotypes. After a 4-week run-in period with ivacaftor or tezacaftor-ivacaftor, patients were randomly assigned to receive elexacaftor-tezacaftor-ivacaftor or active control for 8 weeks. The primary end point was the absolute change in the percentage of predicted forced expiratory volume in 1 second (FEV1) from baseline through week 8 in the elexacaftor-tezacaftor-ivacaftor group. RESULTS: After the run-in period, 132 patients received elexacaftor-tezacaftor-ivacaftor and 126 received active control. Elexacaftor-tezacaftor-ivacaftor resulted in a percentage of predicted FEV1 that was higher by 3.7 percentage points (95% confidence interval [CI], 2.8 to 4.6) relative to baseline and higher by 3.5 percentage points (95% CI, 2.2 to 4.7) relative to active control and a sweat chloride concentration that was lower by 22.3 mmol per liter (95% CI, 20.2 to 24.5) relative to baseline and lower by 23.1 mmol per liter (95% CI, 20.1 to 26.1) relative to active control (P<0.001 for all comparisons). The change from baseline in the Cystic Fibrosis Questionnaire-Revised respiratory domain score (range, 0 to 100, with higher scores indicating better quality of life) with elexacaftor-tezacaftor-ivacaftor was 10.3 points (95% CI, 8.0 to 12.7) and with active control was 1.6 points (95% CI, -0.8 to 4.1). The incidence of adverse events was similar in the two groups; adverse events led to treatment discontinuation in one patient (elevated aminotransferase level) in the elexacaftor-tezacaftor-ivacaftor group and in two patients (anxiety or depression and pulmonary exacerbation) in the active control group. CONCLUSIONS: Elexacaftor-tezacaftor-ivacaftor was efficacious and safe in patients with Phe508del-gating or Phe508del-residual function genotypes and conferred additional benefit relative to previous CFTR modulators. (Funded by Vertex Pharmaceuticals; VX18-445-104 ClinicalTrials.gov number, NCT04058353.).


Assuntos
Aminofenóis/uso terapêutico , Benzodioxóis/uso terapêutico , Agonistas dos Canais de Cloreto/uso terapêutico , Fibrose Cística/tratamento farmacológico , Indóis/uso terapêutico , Pirazóis/uso terapêutico , Piridinas/uso terapêutico , Quinolinas/uso terapêutico , Adolescente , Adulto , Aminofenóis/efeitos adversos , Benzodioxóis/efeitos adversos , Criança , Agonistas dos Canais de Cloreto/efeitos adversos , Cloretos/análise , Fibrose Cística/genética , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Método Duplo-Cego , Combinação de Medicamentos , Feminino , Genótipo , Humanos , Indóis/efeitos adversos , Masculino , Pirazóis/efeitos adversos , Piridinas/efeitos adversos , Quinolinas/efeitos adversos , Suor/química
5.
BMC Cancer ; 21(1): 904, 2021 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-34364385

RESUMO

BACKGROUND: In the phase 3 METEOR trial, cabozantinib improved progression-free survival (PFS) and overall survival (OS) versus everolimus in patients with advanced RCC after prior antiangiogenic therapy. METHODS: In this exploratory analysis, plasma biomarkers from baseline and week 4 from 621 of 658 randomized patients were analyzed for CA9, HGF, MET, GAS6, AXL, VEGF, VEGFR2, and IL-8. PFS and OS were analyzed by baseline biomarker levels as both dichotomized and continuous variables using univariate and multivariable methods. For on-treatment changes, PFS and OS were analyzed using fold change in biomarker levels at week 4. Biomarkers were considered prognostic if p < 0.05 and predictive if pinteraction < 0.05 for the interaction between treatment and biomarker. RESULTS: Hazard ratios for PFS and OS favored cabozantinib versus everolimus for both low and high baseline levels of all biomarkers (hazard ratios ≤0.78). In univariate analyses, low baseline HGF, AXL, and VEGF were prognostic for improvements in both PFS and OS with cabozantinib, and low HGF was prognostic for improvements in both PFS and OS with everolimus. Low AXL was predictive of relative improvement in PFS for cabozantinib versus everolimus. Results were generally consistent when baseline biomarkers were expressed as continuous variables, although none were predictive of benefit with treatment. In multivariable analysis, low baseline HGF was independently prognostic for improved PFS for both cabozantinib and everolimus; low HGF, GAS6, and VEGF were independently prognostic for improved OS with cabozantinib. No biomarkers were independently prognostic for OS with everolimus. On-treatment increases in some biomarkers appeared prognostic for PFS or OS with cabozantinib in univariate analyses; however, none were independently prognostic in multivariable analysis. CONCLUSIONS: PFS and OS were improved with cabozantinib versus everolimus at high and low baseline levels of all biomarkers. Low baseline HGF was consistently identified as a prognostic biomarker for improved PFS or OS with cabozantinib or everolimus, supporting further prospective evaluation of the prognostic significance of HGF in advanced RCC. TRIAL REGISTRATION: ClinicalTrials.gov NCT01865747 (registered on 05/31/2013).


Assuntos
Anilidas/uso terapêutico , Biomarcadores Tumorais/sangue , Carcinoma de Células Renais/sangue , Carcinoma de Células Renais/tratamento farmacológico , Everolimo/uso terapêutico , Neoplasias Renais/sangue , Neoplasias Renais/tratamento farmacológico , Piridinas/uso terapêutico , Anilidas/administração & dosagem , Anilidas/efeitos adversos , Carcinoma de Células Renais/diagnóstico , Carcinoma de Células Renais/mortalidade , Everolimo/administração & dosagem , Everolimo/efeitos adversos , Humanos , Estimativa de Kaplan-Meier , Neoplasias Renais/diagnóstico , Neoplasias Renais/mortalidade , Prognóstico , Piridinas/administração & dosagem , Piridinas/efeitos adversos , Retratamento , Resultado do Tratamento
6.
Int J Mol Sci ; 22(14)2021 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-34299092

RESUMO

Hutchinson-Gilford progeria syndrome (HGPS) is an ultra-rare multisystem premature aging disorder that leads to early death (mean age of 14.7 years) due to myocardial infarction or stroke. Most cases have a de novo point mutation at position G608G within exon 11 of the LMNA gene. This mutation leads to the production of a permanently farnesylated truncated prelamin A protein called "progerin" that is toxic to the cells. Recently, farnesyltransferase inhibitor (FTI) lonafarnib has been approved by the FDA for the treatment of patients with HGPS. While lonafarnib treatment irrefutably ameliorates HGPS disease, it is however not a cure. FTI has been shown to cause several cellular side effects, including genomic instability as well as binucleated and donut-shaped nuclei. We report that, in addition to these cellular stresses, FTI caused an increased frequency of cytosolic DNA fragment formation. These extranuclear DNA fragments colocalized with cGAs and activated the cGAS-STING-STAT1 signaling axis, upregulating the expression of proinflammatory cytokines in FTI-treated human HGPS fibroblasts. Treatment with lonafarnib and baricitinib, a JAK-STAT inhibitor, not only prevented the activation of the cGAS STING-STAT1 pathway, but also improved the overall HGPS cellular homeostasis. These ameliorations included progerin levels, nuclear shape, proteostasis, cellular ATP, proliferation, and the reduction of cellular inflammation and senescence. Thus, we suggest that combining lonafarnib with baricitinib might provide an opportunity to reduce FTI cellular toxicity and ameliorate HGPS symptoms further than lonafarnib alone.


Assuntos
Azetidinas/farmacologia , Inibidores Enzimáticos/farmacologia , Janus Quinase 1/antagonistas & inibidores , Inibidores de Janus Quinases/farmacologia , Piperidinas/efeitos adversos , Progéria/tratamento farmacológico , Purinas/farmacologia , Pirazóis/farmacologia , Piridinas/efeitos adversos , Fator de Transcrição STAT1/antagonistas & inibidores , Sulfonamidas/farmacologia , Adolescente , Células Cultivadas , Pré-Escolar , Farnesiltranstransferase/efeitos adversos , Feminino , Humanos , Masculino , Progéria/induzido quimicamente , Progéria/patologia
7.
N Engl J Med ; 384(25): 2371-2381, 2021 06 24.
Artigo em Inglês | MEDLINE | ID: mdl-34096690

RESUMO

BACKGROUND: Sotorasib showed anticancer activity in patients with KRAS p.G12C-mutated advanced solid tumors in a phase 1 study, and particularly promising anticancer activity was observed in a subgroup of patients with non-small-cell lung cancer (NSCLC). METHODS: In a single-group, phase 2 trial, we investigated the activity of sotorasib, administered orally at a dose of 960 mg once daily, in patients with KRAS p.G12C-mutated advanced NSCLC previously treated with standard therapies. The primary end point was objective response (complete or partial response) according to independent central review. Key secondary end points included duration of response, disease control (defined as complete response, partial response, or stable disease), progression-free survival, overall survival, and safety. Exploratory biomarkers were evaluated for their association with response to sotorasib therapy. RESULTS: Among the 126 enrolled patients, the majority (81.0%) had previously received both platinum-based chemotherapy and inhibitors of programmed death 1 (PD-1) or programmed death ligand 1 (PD-L1). According to central review, 124 patients had measurable disease at baseline and were evaluated for response. An objective response was observed in 46 patients (37.1%; 95% confidence interval [CI], 28.6 to 46.2), including in 4 (3.2%) who had a complete response and in 42 (33.9%) who had a partial response. The median duration of response was 11.1 months (95% CI, 6.9 to could not be evaluated). Disease control occurred in 100 patients (80.6%; 95% CI, 72.6 to 87.2). The median progression-free survival was 6.8 months (95% CI, 5.1 to 8.2), and the median overall survival was 12.5 months (95% CI, 10.0 to could not be evaluated). Treatment-related adverse events occurred in 88 of 126 patients (69.8%), including grade 3 events in 25 patients (19.8%) and a grade 4 event in 1 (0.8%). Responses were observed in subgroups defined according to PD-L1 expression, tumor mutational burden, and co-occurring mutations in STK11, KEAP1, or TP53. CONCLUSIONS: In this phase 2 trial, sotorasib therapy led to a durable clinical benefit without new safety signals in patients with previously treated KRAS p.G12C-mutated NSCLC. (Funded by Amgen and the National Institutes of Health; CodeBreaK100 ClinicalTrials.gov number, NCT03600883.).


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Piperazinas/uso terapêutico , Proteínas Proto-Oncogênicas p21(ras)/antagonistas & inibidores , Piridinas/uso terapêutico , Pirimidinas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/metabolismo , Biomarcadores/sangue , Carcinoma Pulmonar de Células não Pequenas/genética , Feminino , Humanos , Neoplasias Pulmonares/genética , Masculino , Pessoa de Meia-Idade , Mutação , Piperazinas/efeitos adversos , Intervalo Livre de Progressão , Piridinas/efeitos adversos , Pirimidinas/efeitos adversos
8.
Lancet Oncol ; 22(7): 959-969, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34118197

RESUMO

BACKGROUND: Oncogenic alterations in RET have been identified in multiple tumour types, including 1-2% of non-small-cell lung cancers (NSCLCs). We aimed to assess the safety, tolerability, and antitumour activity of pralsetinib, a highly potent, oral, selective RET inhibitor, in patients with RET fusion-positive NSCLC. METHODS: ARROW is a multi-cohort, open-label, phase 1/2 study done at 71 sites (community and academic cancer centres) in 13 countries (Belgium, China, France, Germany, Hong Kong, Italy, Netherlands, Singapore, South Korea, Spain, Taiwan, the UK, and the USA). Patients aged 18 years or older with locally advanced or metastatic solid tumours, including RET fusion-positive NSCLC, and an Eastern Cooperative Oncology Group performance status of 0-2 (later limited to 0-1 in a protocol amendment) were enrolled. In phase 2, patients received 400 mg once-daily oral pralsetinib, and could continue treatment until disease progression, intolerance, withdrawal of consent, or investigator decision. Phase 2 primary endpoints were overall response rate (according to Response Evaluation Criteria in Solid Tumours version 1·1 and assessed by blinded independent central review) and safety. Tumour response was assessed in patients with RET fusion-positive NSCLC and centrally adjudicated baseline measurable disease who had received platinum-based chemotherapy or were treatment-naive because they were ineligible for standard therapy. This ongoing study is registered with ClinicalTrials.gov, NCT03037385, and enrolment of patients with treatment-naive RET fusion-positive NSCLC was ongoing at the time of this interim analysis. FINDINGS: Of 233 patients with RET fusion-positive NSCLC enrolled between March 17, 2017, and May 22, 2020 (data cutoff), 92 with previous platinum-based chemotherapy and 29 who were treatment-naive received pralsetinib before July 11, 2019 (efficacy enrolment cutoff); 87 previously treated patients and 27 treatment-naive patients had centrally adjudicated baseline measurable disease. Overall responses were recorded in 53 (61%; 95% CI 50-71) of 87 patients with previous platinum-based chemotherapy, including five (6%) patients with a complete response; and 19 (70%; 50-86) of 27 treatment-naive patients, including three (11%) with a complete response. In 233 patients with RET fusion-positive NSCLC, common grade 3 or worse treatment-related adverse events were neutropenia (43 patients [18%]), hypertension (26 [11%]), and anaemia (24 [10%]); there were no treatment-related deaths in this population. INTERPRETATION: Pralsetinib is a new, well-tolerated, promising, once-daily oral treatment option for patients with RET fusion-positive NSCLC. FUNDING: Blueprint Medicines.


Assuntos
Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/genética , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Fusão Gênica , Neoplasias Pulmonares/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas c-ret/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-ret/genética , Pirazóis/uso terapêutico , Piridinas/uso terapêutico , Pirimidinas/uso terapêutico , Idoso , Antineoplásicos/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Feminino , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Inibidores de Proteínas Quinases/efeitos adversos , Pirazóis/efeitos adversos , Piridinas/efeitos adversos , Pirimidinas/efeitos adversos , Fatores de Tempo , Resultado do Tratamento
10.
Expert Opin Investig Drugs ; 30(8): 893-901, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34176392

RESUMO

BACKGROUND: Balovaptan is a potent, selective vasopressin 1a receptor antagonist. The early-phase pharmacokinetics (PK) of balovaptan are reported. RESEARCH DESIGN AND METHODS: Two Phase 1 studies (overall N = 93) assessed single- and multiple-dose balovaptan PK in healthy adults. One (N = 16) assessed absolute oral bioavailability (10 mg or 50 mg) vs a [13C]-balovaptan microdose. The other (N = 77) explored single- (0.5-76 mg) and multiple-dose (14 days; 12-52 mg/day) - randomized 6:2 balovaptan:placebo per dose - PK, dose proportionality, and the effect of food on single-dose (32 mg) Cmax and AUCinf. RESULTS: Absolute balovaptan bioavailability was high (103-116%). Steady-state (Day 14) balovaptan PK was approximately dose proportional with a half-life of 45-47 hours, but single-dose Cmax increased more than dose proportionally and half-life was inversely dose-proportional - a discordance partially attributable to a dose-and-time-dependent volume of distribution. Accumulation (Day 1-Day 14) was inversely dose-proportional (~3.5 [12 mg] to ~1.8 [52 mg]). There was no relevant effect of a high-fat meal on single-dose balovaptan exposure. There were no safety signals: 2/93 subjects discontinued for adverse events. CONCLUSIONS: Balovaptan was well tolerated at single (≤76 mg) and multiple (≤52 mg/day) doses, with a PK profile supportive of once-daily administration without food restrictions. TRIAL REGISTRATION: ClinicalTrials.gov NCT03764449; NCT01418963.


Assuntos
Antagonistas dos Receptores de Hormônios Antidiuréticos/administração & dosagem , Benzodiazepinas/administração & dosagem , Interações Alimento-Droga , Piridinas/administração & dosagem , Triazóis/administração & dosagem , Administração Oral , Adolescente , Adulto , Antagonistas dos Receptores de Hormônios Antidiuréticos/efeitos adversos , Antagonistas dos Receptores de Hormônios Antidiuréticos/farmacocinética , Área Sob a Curva , Benzodiazepinas/efeitos adversos , Benzodiazepinas/farmacocinética , Disponibilidade Biológica , Estudos Cross-Over , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Meia-Vida , Humanos , Masculino , Pessoa de Meia-Idade , Piridinas/efeitos adversos , Piridinas/farmacocinética , Fatores de Tempo , Distribuição Tecidual , Triazóis/efeitos adversos , Triazóis/farmacocinética , Adulto Jovem
11.
N Engl J Med ; 385(1): 35-45, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34192430

RESUMO

BACKGROUND: In celiac disease, small intestinal transglutaminase 2 causes deamidation of glutamine residues in gluten peptides, which enhances stimulation of T cells and leads to mucosal injury. Inhibition of transglutaminase 2 is a potential treatment for celiac disease. METHODS: In a proof-of-concept trial, we assessed the efficacy and safety of a 6-week treatment with ZED1227, a selective oral transglutaminase 2 inhibitor, at three dose levels as compared with placebo, in adults with well-controlled celiac disease who underwent a daily gluten challenge. The primary end point was the attenuation of gluten-induced mucosal damage, as measured by the ratio of villus height to crypt depth. Secondary end points included intraepithelial lymphocyte density, the Celiac Symptom Index score, and the Celiac Disease Questionnaire score (for assessment of health-related quality of life). RESULTS: Of the 41 patients assigned to the 10-mg ZED1227 group, the 41 assigned to the 50-mg group, the 41 assigned to the 100-mg group, and the 40 assigned to the placebo group, 35, 39, 38, and 30 patients, respectively, had adequate duodenal-biopsy samples for the assessment of the primary end point. Treatment with ZED1227 at all three dose levels attenuated gluten-induced duodenal mucosal injury. The estimated difference from placebo in the change in the mean ratio of villus height to crypt depth from baseline to week 6 was 0.44 (95% confidence interval [CI], 0.15 to 0.73) in the 10-mg group (P = 0.001), 0.49 (95% CI, 0.20 to 0.77) in the 50-mg group (P<0.001), and 0.48 (95% CI, 0.20 to 0.77) in the 100-mg group (P<0.001). The estimated differences from placebo in the change in intraepithelial lymphocyte density were -2.7 cells per 100 epithelial cells (95% CI, -7.6 to 2.2) in the 10-mg group, -4.2 cells per 100 epithelial cells (95% CI, -8.9 to 0.6) in the 50-mg group, and -9.6 cells per 100 epithelial cells (95% CI, -14.4 to -4.8) in the 100-mg group. Use of the 100-mg dose may have improved symptom and quality-of-life scores. The most common adverse events, the incidences of which were similar across all groups, were headache, nausea, diarrhea, vomiting, and abdominal pain. Rash developed in 3 of 40 patients (8%) in the 100-mg group. CONCLUSIONS: In this preliminary trial, treatment with ZED1227 attenuated gluten-induced duodenal mucosal damage in patients with celiac disease. (Funded by Dr. Falk Pharma; CEC-3 EudraCT number, 2017-002241-30.).


Assuntos
Doença Celíaca/tratamento farmacológico , Duodeno/patologia , Proteínas de Ligação ao GTP/antagonistas & inibidores , Imidazóis/administração & dosagem , Mucosa Intestinal/patologia , Piridinas/administração & dosagem , Transglutaminases/antagonistas & inibidores , Administração Oral , Adulto , Doença Celíaca/patologia , Relação Dose-Resposta a Droga , Método Duplo-Cego , Duodeno/imunologia , Feminino , Glutens/administração & dosagem , Glutens/efeitos adversos , Humanos , Imidazóis/efeitos adversos , Mucosa Intestinal/imunologia , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Estudo de Prova de Conceito , Piridinas/efeitos adversos , Qualidade de Vida , Índice de Gravidade de Doença
12.
Lancet Oncol ; 22(6): 848-857, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34000246

RESUMO

BACKGROUND: Before February, 2021, there was no standard treatment regimen for locally advanced basal cell carcinoma after first-line hedgehog inhibitor (HHI) therapy. Cemiplimab, a PD-1 antibody, is approved for treatment of advanced cutaneous squamous cell carcinoma and has shown clinical activity as monotherapy in first-line non-small-cell lung cancer. Here, we present the primary analysis data of cemiplimab in patients with locally advanced basal cell carcinoma after HHI therapy. METHODS: We did an open-label, multicentre, single-arm, phase 2 trial across 38 outpatient clinics, primarily at academic medical centres, in Canada, Europe, and the USA. Eligible patients (aged ≥18 years and with an Eastern Cooperative Oncology Group performance status of 0 or 1) with a histologically confirmed diagnosis of metastatic basal cell carcinoma (group 1) or locally advanced basal cell carcinoma (group 2) who had progressed on or were intolerant to previous HHI therapy were enrolled. Patients were not candidates for further HHI therapy due to progression of disease on or intolerance to previous HHI therapy or having no better than stable disease after 9 months on HHI therapy. Patients received cemiplimab 350 mg intravenously every 3 weeks for up to 93 weeks or until progression or unacceptable toxicity. The primary endpoint was objective response by independent central review. Analyses were done as per the intention-to-treat principle. The safety analysis comprised all patients who received at least one dose of cemiplimab. The primary analysis is reported only for group 2; group 1 data have not reached maturity and will be reported when the timepoint, according to the statistical analysis plan, has been reached. This study is registered with ClinicalTrials.gov, NCT03132636, and is no longer recruiting new participants. FINDINGS: Between Nov 16, 2017, and Jan 7, 2019, 84 patients were enrolled and treated with cemiplimab. At data cutoff on Feb 17, 2020, median duration of follow-up was 15 months (IQR 8-18). An objective response per independent central review was observed in 26 (31%; 95% CI 21-42) of 84 patients, including two partial responses that emerged at tumour assessments before the data cutoff and were confirmed by tumour assessments done subsequent to the data cutoff. The best overall response was five (6%) patients with a complete response and 21 (25%) with a partial response. Grade 3-4 treatment-emergent adverse events occurred in 40 (48%) of 84 patients; the most common were hypertension (four [5%] of 84 patients) and colitis (four [5%]). Serious treatment-emergent adverse events occurred in 29 (35%) of 84 patients. There were no treatment-related deaths. INTERPRETATION: Cemiplimab exhibited clinically meaningful antitumour activity and an acceptable safety profile in patients with locally advanced basal cell carcinoma after HHI therapy. FUNDING: Regeneron Pharmaceuticals and Sanofi.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Carcinoma Basocelular/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Neoplasias Cutâneas/tratamento farmacológico , Adulto , Idoso , Anilidas/administração & dosagem , Anilidas/efeitos adversos , Anticorpos Monoclonais Humanizados/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma Basocelular/genética , Carcinoma Basocelular/patologia , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Proteínas Hedgehog/antagonistas & inibidores , Proteínas Hedgehog/genética , Humanos , Inibidores de Checkpoint Imunológico/administração & dosagem , Inibidores de Checkpoint Imunológico/efeitos adversos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Receptor de Morte Celular Programada 1/genética , Piridinas/administração & dosagem , Piridinas/efeitos adversos , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia
13.
Oncology ; 99(8): 491-498, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34000725

RESUMO

INTRODUCTION: This study compared clinical outcomes of 2nd- and 3rd-line regorafenib in patients with unresectable hepatocellular carcinoma. METHODS: In this retrospective cohort study, 48 patients were treated with regorafenib for unresectable hepatocellular carcinoma. Thirty-five and 13 patients were initiated on 2nd- and 3rd-line therapy, respectively. We assessed the responses to and safety of the therapy. RESULTS: There were no statistically significant differences in clinical characteristics at the start of 2nd- or 3rd-line regorafenib therapy. The overall response rate of 2nd- and 3rd-line regorafenib was 20 and 8%, respectively. The disease control rate was 57 and 54%, respectively. Median overall survival (mOS) from the start of 2nd-line regorafenib was 17.5 months. mOS from the start of 3rd-line regorafenib was not obtained. Median progression-free survival of 2nd- and 3rd-line regorafenib was 4.9 and 2.3 months, respectively. mOS from 1st-line therapy with tyrosine kinase inhibitor plus sorafenib-regorafenib-lenvatinib was 29.5 months; that with lenvatinib-sorafenib-regorafenib was not obtained. Patients on 3rd-line therapy tended to have better Child-Pugh scores and tumor factors at the start of 1st-line therapy than other patients. CONCLUSION: Patients on 2nd- and 3rd-line regorafenib showed favorable responses. Good Child-Pugh scores and tumor factors may be associated with a better response rate and OS.


Assuntos
Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Compostos de Fenilureia/administração & dosagem , Piridinas/administração & dosagem , Administração Oral , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Carcinoma Hepatocelular/patologia , Estudos de Coortes , Feminino , Humanos , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Compostos de Fenilureia/efeitos adversos , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Piridinas/efeitos adversos , Quinolinas/administração & dosagem , Quinolinas/efeitos adversos , Estudos Retrospectivos , Sorafenibe/administração & dosagem , Sorafenibe/efeitos adversos , Taxa de Sobrevida , Resultado do Tratamento
14.
Antimicrob Agents Chemother ; 65(8): e0029021, 2021 07 16.
Artigo em Inglês | MEDLINE | ID: mdl-34031051

RESUMO

Isavuconazole, administered as the water-soluble prodrug isavuconazonium sulfate, is a new triazole agent used to treat invasive fungal infections. This phase 1 study evaluated the pharmacokinetics (PK), safety, and tolerability of isavuconazole in 46 immunocompromised pediatric patients, stratified by age (1 to <6 [intravenous (i.v.) only], 6 to <12, and 12 to <18 years), receiving 10 mg/kg body weight (maximum, 372 mg) isavuconazonium sulfate either i.v. or orally. A population PK model using weight-based allometric scaling was constructed with the pediatric i.v. and oral data plus i.v. data from a phase 1 study in adults. The best model was a 3-compartment model with combined zero-order and first-order input, with linear elimination. Stepwise covariate modeling was performed in Perl-speaks-NONMEM version 4.7.0. None of the covariates examined, including age, sex, race, and body mass index, were statistically significant for any of the PK parameters. The area under the concentration-time curve at steady state (AUCSS) was predicted for pediatric patients using 1,000 Monte Carlo simulations per age cohort for each administration route. The probability of target attainment (AUCSS range, 60 to 233 µg · h/ml) was estimated; this target range was derived from plasma drug exposures in adults receiving the recommended clinical dose. Predicted plasma drug exposures were within the target range for >80% and >76% of simulated pediatric patients following i.v. or oral administration, respectively. Intravenous and oral administration of isavuconazonium sulfate at the studied dosage of 10 mg/kg was well tolerated and resulted in exposure in pediatric patients similar to that in adults. (This study has been registered at ClinicalTrials.gov under identifier NCT03241550).


Assuntos
Infecções Fúngicas Invasivas , Triazóis , Administração Oral , Adolescente , Criança , Pré-Escolar , Humanos , Lactente , Infecções Fúngicas Invasivas/tratamento farmacológico , Nitrilas/uso terapêutico , Piridinas/efeitos adversos , Triazóis/uso terapêutico
15.
J Drugs Dermatol ; 20(5): 552-554, 2021 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-33938701

RESUMO

Locally-advanced periocular basal cell carcinoma (BCC) pose many therapeutic challenges due to the need to preserve functionality and cosmesis of the orbit and periocular area. Surgical excision and subsequent orbital exenteration are two recognized modalities of treatment. Vismodegib is currently an FDA-approved monotherapy for locally-advanced and metastatic BCC. We present a case of the use of vismodegib as neoadjuvant therapy prior to surgical excision of a locally-advanced periocular recurrent BCC in a 75-year-old male. The patient’s tumor successfully responded to vismodegib allowing surgical excision with clear margins. The orbit was saved in a patient who otherwise would have required complete orbital exenteration. J Drugs Dermatol. 20(5):552-554. doi:10.36849/JDD.5661.


Assuntos
Anilidas/administração & dosagem , Carcinoma Basocelular/terapia , Neoplasias Palpebrais/terapia , Recidiva Local de Neoplasia/terapia , Piridinas/administração & dosagem , Neoplasias Cutâneas/terapia , Administração Oral , Idoso , Anilidas/efeitos adversos , Carcinoma Basocelular/diagnóstico , Carcinoma Basocelular/patologia , Neoplasias Palpebrais/diagnóstico , Neoplasias Palpebrais/patologia , Pálpebras/diagnóstico por imagem , Pálpebras/patologia , Pálpebras/cirurgia , Humanos , Imageamento por Ressonância Magnética , Masculino , Margens de Excisão , Terapia Neoadjuvante/métodos , Recidiva Local de Neoplasia/diagnóstico , Recidiva Local de Neoplasia/patologia , Tratamentos com Preservação do Órgão/métodos , Piridinas/efeitos adversos , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/patologia , Resultado do Tratamento
16.
Methods Mol Biol ; 2299: 339-356, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34028753

RESUMO

Liver fibrosis is defined as excessive accumulation of extracellular matrix, and results from maladaptive wound healing processes that occur in response to chronic liver injury and inflammation. The main etiologies of liver fibrosis include nonalcoholic fatty liver disease (NAFLD), chronic viral hepatitis, as well as alcoholic and cholestatic liver disease. In patients, liver fibrosis typically develops over several decades and can progress to cirrhosis, and liver failure due to replacement of functional liver tissue with scar tissue. Additionally, advanced fibrosis and cirrhosis are associated with an increased risk for the development of hepatocellular carcinoma. On a cellular level, hepatic fibrosis is mediated by activated hepatic stellate cells, the primary fibrogenic cell type of the liver. Murine models are employed to recapitulate, understand, and therapeutically target mechanisms of fibrosis and hepatic stellate cell activation. Here, we summarize different mouse models of liver fibrosis focusing on the most commonly used models of toxic, biliary, and metabolically induced liver fibrosis, triggered by treatment with carbon tetrachloride (CCl4), thioacetamide (TAA), bile duct ligation (BDL), 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC), and high-fat diets.


Assuntos
Células Estreladas do Fígado/patologia , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/patologia , Animais , Tetracloreto de Carbono/efeitos adversos , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Células Estreladas do Fígado/efeitos dos fármacos , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Piridinas/efeitos adversos , Tioacetamida/efeitos adversos
17.
BMC Cancer ; 21(1): 564, 2021 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-34001059

RESUMO

BACKGROUND: The chemotherapy triplet FOLFOXIRI combined to the anti-VEGF antibody bevacizumab is an option in selected patients with metastatic colorectal cancer. In this setting, RAS-mutated metastatic colorectal cancer do not benefit the same from treatment than RAS-wildtype metastatic colorectal cancer do. Together with its antiangiogenic properties, the tyrosine-kinase inhibitor regorafenib has also anti-proliferative activities whatever the RAS status is. The present trial aims at studying the safety and the efficacy of regorafenib in combination with FOLFIRINOX - a chemotherapy triplet using a different dosing schedule than FOLFOXIRI - in patients with RAS-mutated metastatic colorectal cancer. METHODS: FOLFIRINOX-R is a prospective, multicentric, non-randomised, dose-finding phase 1-2 trial. The primary endpoints are the determination of the maximum tolerated dose, the recommended phase 2 dose, and the proportion of patients achieving disease control at 48-weeks. Phase 1 follows a 3 + 3 design (12 to 24 patients to be included). Sixty nine patients will be necessary in phase 2, including 5% non-evaluable ones, with the following assumptions, one-stage Fleming design, α = 5%, ß = 20%, p0 = 35% and p1 = 50%. Key eligibility criteria include Eastern Cooperative Oncology Group Performance Status of ≤1 and RAS-mutated metastatic colorectal cancer not amenable to surgery with curative intent and not previously treated for metastatic disease. FOLFIRINOX (oxaliplatin 85 mg/m2, folinic acid 400 mg/m2, irinotecan 150-180 mg/m2, 5-fluorouracil: 400 mg/m2 then 2400 mg/m2 over 46 h) is administered every 14 days. Regorafenib (80 to 160 mg, as per dose-level) is administered orally, once daily on days 4 to 10 of each cycle. DISCUSSION: FOLFIRINOX-R is the first phase I/II study to evaluate the safety and efficacy of regorafenib in combination with FOLFIRINOX as frontline therapy for patients with RAS-mutated metastatic colorectal cancer. TRIAL REGISTRATION: EudraCT: 2018-003541-42 ; ClinicalTrials.gov: NCT03828799 .


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias Colorretais/tratamento farmacológico , Compostos de Fenilureia/administração & dosagem , Piridinas/administração & dosagem , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Ensaios Clínicos Fase I como Assunto , Ensaios Clínicos Fase II como Assunto , Neoplasias Colorretais/genética , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Esquema de Medicação , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/efeitos adversos , Humanos , Irinotecano/administração & dosagem , Irinotecano/efeitos adversos , Leucovorina/administração & dosagem , Leucovorina/efeitos adversos , Masculino , Estudos Multicêntricos como Assunto , Oxaliplatina/administração & dosagem , Oxaliplatina/efeitos adversos , Compostos de Fenilureia/efeitos adversos , Intervalo Livre de Progressão , Estudos Prospectivos , Piridinas/efeitos adversos , Adulto Jovem , Proteínas ras/genética
18.
Anticancer Res ; 41(5): 2553-2561, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33952483

RESUMO

BACKGROUND/AIM: Regorafenib (REG) and trifluridine/tipiracil (FTD/TPI) have have been shown to improve overall survival in patients with refractory metastatic colorectal cancer. The aim of our study was to evaluate the efficacy and safety profiles of these agents administered in sequence in real world practice. PATIENTS AND METHODS: Clinical data of patients treated beyond the 2°line with REG or FTD/TPI between January 2016 and August 2020, were retrospectively collected from eight institutes in the Lazio Region. RESULTS: We included 49 patients treated with both drug sequences. A total of 28 G3/G4 toxicity events (53.8%) were recorded in the FTD/TPI-to-REG sequence vs. 24 (46.1%) in the reverse sequence. Median overall survival for the patients included in the FTP/TPI-to-REG group was 20 months (95%CI=16.7-23.3) vs. 27 months in the reverse group (95%CI=17.8-36.2). The disease control rate was 45.0% for patients treated with the REG-to-FTD/TPI sequence vs. 24.1% in those treated with the FTD/TPI-to-REG sequence (p=0.18). CONCLUSION: The sequence REG-to-FTD/TPI and vice versa can extend survival, whereas only REG-to-FTD/TPI stabilizes cancer growth.


Assuntos
Neoplasias Colorretais/tratamento farmacológico , Compostos de Fenilureia/administração & dosagem , Piridinas/administração & dosagem , Pirrolidinas/administração & dosagem , Timina/administração & dosagem , Trifluridina/administração & dosagem , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Esquema de Medicação , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Compostos de Fenilureia/efeitos adversos , Intervalo Livre de Progressão , Piridinas/efeitos adversos , Pirrolidinas/efeitos adversos , Timina/efeitos adversos , Trifluridina/efeitos adversos
19.
Int Heart J ; 62(3): 700-705, 2021 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-33994512

RESUMO

For the past 20 years, S-1 has been used in the treatment of many types of cancer. However, the clinical importance of myocardial dysfunction attributed to S-1 remains to be unclear. Thus, in this study, we report on a patient with myocardial dysfunction associated with S-1.S-1 postoperative chemotherapy for gastric cancer was included as a treatment for a 65-year-old man. On day 8, S-1 treatment was discontinued after the patient developed an oral ulcer. He was then admitted to the hospital because of diarrhea caused by S-1. At approximately the same time, he developed dyspnea, and his chest X-rays revealed perihilar vascular engorgement and cardiac enlargement. Although his brain natriuretic peptide was 595.8 pg/mL, troponin I and creatine phosphokinase were unremarkable. Electrocardiograms showed no change in atrial fibrillations or new ST-T wave change. As per his transthoracic echocardiogram, noted were expansion of the left ventricle, global hypokinesis, and reduced left ventricular ejection fraction (approximately 40%). The patient was then diagnosed with S-1-related myocardial dysfunction. Furosemide, human atrial natriuretic peptide, dobutamine, enalapril, spironolactone, and bisoprolol were administered. Thirteen days after being diagnosed with heart failure, his symptoms disappeared, his echocardiogram showed that the left ventricular ejection fraction had increased to 65%, and the cardiothoracic ratio improved to 47% according to his chest X-rays.S-1-related myocardial dysfunction may be reversible, as it can improve after approximately 2 weeks.


Assuntos
Antimetabólitos Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Cardiotoxicidade/etiologia , Ácido Oxônico/efeitos adversos , Piridinas/efeitos adversos , Tegafur/efeitos adversos , Idoso , Combinação de Medicamentos , Humanos , Masculino , Neoplasias Gástricas/tratamento farmacológico
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