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1.
Eur Rev Med Pharmacol Sci ; 25(16): 5310-5317, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34486707

RESUMO

OBJECTIVE: The outbreak of coronavirus disease 2019 (COVID-19) has affected the treatment of cancer patients, with particular regard to the management of both chemotherapy and side effects. Chemotherapy-induced nausea and vomiting (CINV) are amongst the most troublesome side effects that impair patients' adherence to treatments and their quality of life (QoL). NEPA (Akynzeo®), is an oral fixed-dose combination of netupitant [a neurokinin-1 receptor antagonist (NK1RA), 300 mg] and palonosetron [(5-hydroxytryptamine (serotonin or 5HT) type3 receptor antagonist (5HT3RA), 0.5 mg] which has been shown to be effective in preventing CINV. PATIENTS AND METHODS: This prospective study started before the outbreak of COVID-19 and was carried out during the pandemic period. The aim was to evaluate the efficacy and safety of a single oral dose NEPA plus 12 mg of dexamethasone (DEX) in patients treated with Folfoxiri plus Bevacizumab and Folfirinox. The patients were diagnosed with advanced colorectal cancer (CRC) or advanced pancreatic ductal adenocarcinoma (PDAC). They were divided into two groups: naïve patients and patients previously treated with serotonin receptor antagonists (5HT3-RA) and neurokin-1 receptor antagonists (NK1-RA). RESULTS: During the overall phase, the complete response (CR) rate was 96.8% in naïve patients treated with Folfoxiri plus Bevacizumab, and 94.6% in patients treated with Folfirinox. During the acute and delayed phases, the CR rate was 92.8% and 94.2%, with Folfoxiri and Bevacizumab, as well as 96.2% and 94.6%, with Folfirinox. There was no adequate control of CINV events in patients on antiemetic prophylaxis with 5HT3-RA or NK1-RA associated with cortisone. During the overall phase, the CR rate was 74.6% with Folfoxiri plus Bevacizumab and 75.8% with Folfirinox. During the acute and delayed phases, the CR rate was 72.5% and 74.8% with Folfoxiri plus Bevacizumab, as well as 75.2% and 74.6% with Folfirinox. CONCLUSIONS: This study has shown the therapeutic benefits of NEPA in the management and prophylaxis of CINV events, both in naive patients and patients previously treated with 5HT3-RA and NK1-RA. In addition, NEPA has been shown to be safe, both before and during the COVID-19 pandemic.


Assuntos
Antieméticos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bevacizumab/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Palonossetrom/uso terapêutico , Piridinas/uso terapêutico , Idoso , Antieméticos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Bevacizumab/administração & dosagem , COVID-19 , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/uso terapêutico , Humanos , Irinotecano/administração & dosagem , Irinotecano/uso terapêutico , Leucovorina/administração & dosagem , Leucovorina/uso terapêutico , Masculino , Pessoa de Meia-Idade , Náusea/prevenção & controle , Oxaliplatina/administração & dosagem , Oxaliplatina/uso terapêutico , Palonossetrom/administração & dosagem , Pandemias , Estudos Prospectivos , Piridinas/administração & dosagem , Vômito/prevenção & controle
2.
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
3.
Molecules ; 26(16)2021 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-34443460

RESUMO

Synthetic heterocyclic compounds have incredible potential against different diseases; pyridines, phenolic compounds and the derivatives of azo moiety have shown excellent antimicrobial, antiviral, antidiabetic, anti-melanogenic, anti-ulcer, anticancer, anti-mycobacterial, anti-inflammatory, DNA binding and chemosensing activities. In the present review, the above-mentioned activities of the nitrogen-containing heterocyclic compounds (pyridines), hydroxyl (phenols) and azo derivatives are discussed with reference to the minimum inhibitory concentration and structure-activity relationship, which clearly indicate that the presence of nitrogen in the phenyl ring; in addition, the hydroxyl substituent and the incorporation of a diazo group is crucial for the improved efficacies of the compounds in probing different diseases. The comparison was made with the reported drugs and new synthetic derivatives that showed recent therapeutic perspectives made in the last five years.


Assuntos
Compostos Azo/uso terapêutico , Fenóis/uso terapêutico , Piridinas/uso terapêutico , Compostos Azo/síntese química , Compostos Azo/química , Imageamento Tridimensional , Fenóis/síntese química , Fenóis/química , Piridinas/síntese química , Piridinas/química
4.
Int J Mol Sci ; 22(16)2021 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-34445318

RESUMO

Recent studies revealed that the activation of serotonergic 5-HT1A and muscarinic M1, M4, or M5 receptors prevent MK-801-induced cognitive impairments in animal models. In the present study, the effectiveness of the simultaneous activation of 5-HT1A and muscarinic receptors at preventing MK-801-induced cognitive deficits in novel object recognition (NOR) or Y-maze tests was investigated. Activators of 5-HT1A (F15599), M1 (VU0357017), M4 (VU0152100), or M5 (VU0238429) receptors administered at top doses for seven days reversed MK-801-induced deficits in the NOR test, similar to the simultaneous administration of subeffective doses of F15599 (0.05 mg/kg) with VU0357017 (0.15 mg/kg), VU0152100 (0.05 mg/kg), or VU0238429 (1 mg/kg). The compounds did not prevent the MK-801-induced impairment when administered acutely. Their activity was less evident in the Y-maze. Pharmacokinetic studies revealed high brain penetration of F15599 (brain/plasma ratio 620%), which was detected in the frontal cortex (FC) up to 2 h after administration. Decreases in the brain penetration properties of the compounds were observed after acute administration of the combinations, which might have influenced behavioral responses. This negative effect on brain penetration was not observed when the compounds were administered repeatedly. Based on our results, prolonged administration of a 5-HT1A activator with muscarinic receptor ligands may be effective at reversing cognitive decline related to schizophrenia, and the FC may play a critical role in this interaction.


Assuntos
Colinérgicos/farmacologia , Disfunção Cognitiva/tratamento farmacológico , Córtex Pré-Frontal/efeitos dos fármacos , Esquizofrenia/tratamento farmacológico , Agonistas do Receptor de Serotonina/farmacologia , Animais , Benzamidas/farmacocinética , Benzamidas/farmacologia , Benzamidas/uso terapêutico , Barreira Hematoencefálica/metabolismo , Colinérgicos/farmacocinética , Colinérgicos/uso terapêutico , Disfunção Cognitiva/etiologia , Maleato de Dizocilpina/toxicidade , Masculino , Aprendizagem em Labirinto , Camundongos , Piperidinas/farmacocinética , Piperidinas/farmacologia , Piperidinas/uso terapêutico , Córtex Pré-Frontal/metabolismo , Piridinas/farmacocinética , Piridinas/farmacologia , Piridinas/uso terapêutico , Pirimidinas/farmacocinética , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Receptores Muscarínicos/metabolismo , Receptores de Serotonina/metabolismo , Esquizofrenia/complicações , Agonistas do Receptor de Serotonina/farmacocinética , Agonistas do Receptor de Serotonina/uso terapêutico , Tiofenos/farmacocinética , Tiofenos/farmacologia , Tiofenos/uso terapêutico
5.
J Clin Neurosci ; 90: 82-88, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34275586

RESUMO

OBJECTIVES: Recurrent high-grade glioma, a malignant tumor of the brain or spinal cord associated with poor prognosis with a median survival of <6 months. Recurrent high-grade glioma does not have standard treatment even if some strategies have some effect in recurrent gliomas. Apatinib, as a tyrosine kinase inhibitor shown to be effective in treating the lung and gastric cancer. The present study investigated the efficacy and safety of apatinib in combination with dose-dense regimens of temozolomide for treating recurrent glioma. PATIENTS AND METHODS: Eighteen patients with recurrent high-grade glioma were enrolled and treated with apatinib (500 mg/day) and TMZ (50 mg/m2/day). Patients who achieved partial response or stable disease continued treatment. Administration of drug was terminated for patients with progressive disease, who could not tolerate toxicity, and who required discontinuation due to other medical conditions. RESULTS: From the 18 cases, only 17 were included in the evaluation of the curative effect of the drug and in that four showed partial responses, ten had stable disease, remaining three exhibited progressive disease. The disease control rate was 82.3% (14/17). Progression-free and overall survival was found to be 4 months and 9.1 months, respectively. Three patients became transiently capable of self-care (Karnofsky performance status >70). Cognition and quality of life improved after treatment and from the safety perspective, three most common adverse reactions included epilepsy (24.1%), hypertension (20.7%), and fatigue (17.2%). CONCLUSION: Apatinib and TMZ may represent an alternative treatment option for patients with recurrent high-gradeglioma, especially those with a low Karnofsky performance status. However, studies using a larger sample size are required to confirm these findings.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Glioma/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Piridinas/uso terapêutico , Temozolomida/uso terapêutico , Adolescente , Adulto , Idoso , Antineoplásicos Alquilantes/uso terapêutico , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/patologia , Quimioterapia Combinada , Feminino , Glioma/mortalidade , Glioma/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/mortalidade , Recidiva Local de Neoplasia/patologia , Qualidade de Vida , Taxa de Sobrevida , Resultado do Tratamento
6.
Clin Drug Investig ; 41(8): 741-749, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34304373

RESUMO

Filgotinib (Jyseleca®), an oral Janus kinase (JAK) inhibitor, is approved as monotherapy or in combination with methotrexate to treat moderate to severe active rheumatoid arthritis (RA) in adults who have an inadequate response or intolerance to one or more disease-modifying antirheumatic drugs (DMARDs). In phase 3 trials, once-daily filgotinib was generally well tolerated and associated with an improvement in RA signs and symptoms as well as physical function in patients with an inadequate response to ongoing methotrexate, an inadequate response to ongoing conventional synthetic DMARDs plus an inadequate response or intolerance to prior biologic DMARDs, or limited or no prior exposure to methotrexate. In addition, filgotinib was noninferior to adalimumab in terms of low disease activity response rate (DAS28-CRP ≤ 3.2) in patients with an inadequate response to methotrexate. Filgotinib also appeared to inhibit the radiographic progression of joint damage and led to low disease activity or disease remission (DAS28-CRP < 2.6). Filgotinib showed sustained efficacy, and the safety profile of filgotinib longer term was similar to that in the phase 2 and 3 trials.


Assuntos
Antirreumáticos , Artrite Reumatoide , Adulto , Antirreumáticos/efeitos adversos , Artrite Reumatoide/tratamento farmacológico , Quimioterapia Combinada , Humanos , Piridinas/uso terapêutico , Triazóis
7.
Lancet Oncol ; 22(8): 1126-1138, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34237250

RESUMO

BACKGROUND: Patients with radioiodine-refractory differentiated thyroid cancer (DTC) previously treated with vascular endothelial growth factor receptor (VEGFR)-targeted therapy have aggressive disease and no available standard of care. The aim of this study was to evaluate the tyrosine kinase inhibitor cabozantinib in this patient population. METHODS: In this global, randomised, double-blind, placebo-controlled, phase 3 trial, patients aged 16 years and older with radioiodine-refractory DTC (papillary or follicular and their variants) and an Eastern Cooperative Oncology Group performance status of 0 or 1 were randomly assigned (2:1) to oral cabozantinib (60 mg once daily) or matching placebo, stratified by previous lenvatinib treatment and age. The randomisation scheme used stratified permuted blocks of block size six and an interactive voice-web response system; both patients and investigators were masked to study treatment. Patients must have received previous lenvatinib or sorafenib and progressed during or after treatment with up to two VEGFR tyrosine kinase inhibitors. Patients receiving placebo could cross over to open-label cabozantinib on disease progression confirmed by blinded independent radiology committee (BIRC). The primary endpoints were objective response rate (confirmed response per Response Evaluation Criteria in Solid Tumours [RECIST] version 1.1) in the first 100 randomly assigned patients (objective response rate intention-to-treat [OITT] population) and progression-free survival (time to earlier of disease progression per RECIST version 1.1 or death) in all patients (intention-to-treat [ITT] population), both assessed by BIRC. This report presents the primary objective response rate analysis and a concurrent preplanned interim progression-free survival analysis. The study is registered with ClinicalTrials.gov, NCT03690388, and is no longer enrolling patients. FINDINGS: Between Feb 27, 2019, and Aug 18, 2020, 227 patients were assessed for eligibility, of whom 187 were enrolled from 164 clinics in 25 countries and randomly assigned to cabozantinib (n=125) or placebo (n=62). At data cutoff (Aug 19, 2020) for the primary objective response rate and interim progression-free survival analyses, median follow-up was 6·2 months (IQR 3·4-9·2) for the ITT population and 8·9 months (7·1-10·5) for the OITT population. An objective response in the OITT population was achieved in ten (15%; 99% CI 5·8-29·3) of 67 patients in the cabozantinib group versus 0 (0%; 0-14·8) of 33 in the placebo (p=0·028) but did not meet the prespecified significance level (α=0·01). At interim analysis, the primary endpoint of progression-free survival was met in the ITT population; cabozantinib showed significant improvement in progression-free survival over placebo: median not reached (96% CI 5·7-not estimable [NE]) versus 1·9 months (1·8-3·6); hazard ratio 0·22 (96% CI 0·13-0·36; p<0·0001). Grade 3 or 4 adverse events occurred in 71 (57%) of 125 patients receiving cabozantinib and 16 (26%) of 62 receiving placebo, the most frequent of which were palmar-plantar erythrodysaesthesia (13 [10%] vs 0), hypertension (11 [9%] vs 2 [3%]), and fatigue (ten [8%] vs 0). Serious treatment-related adverse events occurred in 20 (16%) of 125 patients in the cabozantinib group and one (2%) of 62 in the placebo group. There were no treatment-related deaths. INTERPRETATION: Our results show that cabozantinib significantly prolongs progression-free survival and might provide a new treatment option for patients with radioiodine-refractory DTC who have no available standard of care. FUNDING: Exelixis.


Assuntos
Anilidas/uso terapêutico , Piridinas/uso terapêutico , Neoplasias da Glândula Tireoide/tratamento farmacológico , Idoso , Método Duplo-Cego , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Intervalo Livre de Progressão
8.
Int J Nanomedicine ; 16: 4481-4494, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34239300

RESUMO

Purpose: Apatinib (Apa) is a novel anti-vascular endothelial growth factor with the potential to treat diabetic retinopathy (DR); a serious condition leading to visual impairment and blindness. DR treatment relies on invasive techniques associated with various complications. Investigating topical routes for Apa delivery to the posterior eye segment is thus promising but also challenging due to ocular barriers. Hence, the study objective was to develop Apa-loaded bovine serum albumin nanoparticles (Apa-BSA-NPs) coated with hyaluronic acid (HA); a natural polymer possessing unique mucoadhesive and viscoelastic features with the capacity to actively target CD44 positive retinal cells, for topical administration in DR. Methods: Apa-BSA-NPs were prepared by desolvation using glutaraldehyde for cross-linking. HA-coated BSA-NPs were also prepared and HA: NPs ratio optimized. Nanoparticles were characterized for colloidal properties, entrapment efficiency (EE%), in vitro drug release and mucoadhesive potential. In vitro cytotoxicity on rabbit corneal epithelial cells (RCE) was assessed using MTT assay, while efficacy was evaluated in vivo in a diabetic rat model by histopathological examination of the retina by light and transmission electron microscopy. Retinal accumulation of fluorescently labeled BSA-NP and HA-BSA-NP was assessed using confocal microscope scanning. Results: Apa-HA-BSA-NPs prepared under optimal conditions showed size, PdI and zeta potential: 222.2±3.56 nm, 0.221±0.02 and -37.3±1.8 mV, respectively. High EE% (69±1%), biphasic sustained release profile with an initial burst effect and mucoadhesion was attained. No evidence of cytotoxicity was observed on RCE cells. In vivo histopathological studies on DR rat model revealed alleviated retinal micro- and ultrastructural changes in the topical HA-Apa-BSA-NP treated eyes with normal basement membrane and retinal thickness comparable to normal control and intravitreally injected nanoparticles. Improved retinal accumulation for HA-BSA-NP was also observed by confocal microscopy. Conclusion: Findings present HA-Apa-BSA-NPs as a platform for enhanced topical therapy of DR overcoming the devastating ocular complications of the intravitreal route.


Assuntos
Retinopatia Diabética/metabolismo , Portadores de Fármacos/química , Ácido Hialurônico/química , Nanopartículas/química , Piridinas/administração & dosagem , Piridinas/química , Soroalbumina Bovina/química , Animais , Retinopatia Diabética/tratamento farmacológico , Liberação Controlada de Fármacos , Tamanho da Partícula , Piridinas/metabolismo , Piridinas/uso terapêutico , Coelhos , Ratos , Retina/metabolismo
9.
Int J Mol Sci ; 22(13)2021 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-34281245

RESUMO

Hutchinson-Gilford progeria syndrome (HGPS), or progeria, is an extremely rare disorder that belongs to the class of laminopathies, diseases characterized by alterations in the genes that encode for the lamin proteins or for their associated interacting proteins. In particular, progeria is caused by a point mutation in the gene that codifies for the lamin A gene. This mutation ultimately leads to the biosynthesis of a mutated version of lamin A called progerin, which accumulates abnormally in the nuclear lamina. This accumulation elicits several alterations at the nuclear, cellular, and tissue levels that are phenotypically reflected in a systemic disorder with important alterations, mainly in the cardiovascular system, bones, skin, and overall growth, which results in premature death at an average age of 14.5 years. In 2020, lonafarnib became the first (and only) FDA approved drug for treating progeria. In this context, the present review focuses on the different therapeutic strategies currently under development, with special attention to the new small molecules described in recent years, which may represent the upcoming first-in-class drugs with new mechanisms of action endowed with effectiveness not only to treat but also to cure progeria.


Assuntos
Piperidinas/uso terapêutico , Progéria/terapia , Piridinas/uso terapêutico , Envelhecimento/genética , Senilidade Prematura/genética , Núcleo Celular/metabolismo , Senescência Celular/genética , Fibroblastos/metabolismo , Humanos , Lamina Tipo A/genética , Laminopatias/terapia , Mutação , Lâmina Nuclear/genética , Lâmina Nuclear/fisiologia , Fenótipo , Progéria/genética , Progéria/metabolismo , Pele/metabolismo , Bibliotecas de Moléculas Pequenas/farmacologia
10.
J Cancer Res Clin Oncol ; 147(10): 2993-3002, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34302208

RESUMO

OBJECTIVE: This study aimed to evaluate the efficacy and safety of regorafenib plus drug-eluting beads-transarterial chemoembolization (DEB-TACE) versus regorafenib monotherapy in colorectal cancer liver metastases (CRLM) patients who failed standard treatment regimens. METHODS: Totally, 76 eligible CRLM patients were analyzed, among which 42 patients received regorafenib monotherapy (as regorafenib group) and 34 patients received regorafenib plus DEB-TACE (as regorafenib plus DEB-TACE group). RESULTS: Objective response rate (35.3% versus 7.1%, P = 0.002) and disease control rate (76.5% versus 47.6%, P = 0.011) were both increased in regorafenib plus DEB-TACE group compared with regorafenib group; meanwhile, negative conversion rate of carcinoembryonic antigen (66.7% versus 28.6%, P = 0.008) after treatment was elevated in regorafenib plus DEB-TACE group compared with regorafenib group. Notably, progression-free survival (PFS) (median value: 7.6 versus 4.1 months, P < 0.001) and overall survival (OS) (median value: 15.7 versus 9.2 months, P < 0.001) were both higher in regorafenib plus DEB-TACE group compared with regorafenib group. Furthermore, liver function indexes (alanine transaminase, aspartate aminotransferase, and cholinesterase levels) after treatment were all similar between the two groups (all P > 0.05). In addition, the occurrences of upper abdominal distending pain (P < 0.001), nausea and vomiting (P = 0.002) and fever (P = 0.002) were higher in regorafenib plus DEB-TACE group compared with regorafenib group, while the majority of these adverse events were mild and tolerable. CONCLUSIONS: Regorafenib plus DEB-TACE is superior to regorafenib monotherapy regarding treatment response, PFS and OS, while induces tolerable post-embolization syndrome in CRLM patients who fail standard treatment regimens.


Assuntos
Quimioembolização Terapêutica/mortalidade , Neoplasias Colorretais/terapia , Sistemas de Liberação de Medicamentos , Neoplasias Hepáticas/terapia , Compostos de Fenilureia/uso terapêutico , Piridinas/uso terapêutico , Terapia de Salvação , Neoplasias Colorretais/patologia , Terapia Combinada , Feminino , Seguimentos , Humanos , Neoplasias Hepáticas/secundário , Masculino , Microesferas , Pessoa de Meia-Idade , Prognóstico , Taxa de Sobrevida
11.
N Engl J Med ; 384(25): 2382-2393, 2021 06 24.
Artigo em Inglês | MEDLINE | ID: mdl-34161704

RESUMO

BACKGROUND: Clinical trials of the KRAS inhibitors adagrasib and sotorasib have shown promising activity in cancers harboring KRAS glycine-to-cysteine amino acid substitutions at codon 12 (KRASG12C). The mechanisms of acquired resistance to these therapies are currently unknown. METHODS: Among patients with KRASG12C -mutant cancers treated with adagrasib monotherapy, we performed genomic and histologic analyses that compared pretreatment samples with those obtained after the development of resistance. Cell-based experiments were conducted to study mutations that confer resistance to KRASG12C inhibitors. RESULTS: A total of 38 patients were included in this study: 27 with non-small-cell lung cancer, 10 with colorectal cancer, and 1 with appendiceal cancer. Putative mechanisms of resistance to adagrasib were detected in 17 patients (45% of the cohort), of whom 7 (18% of the cohort) had multiple coincident mechanisms. Acquired KRAS alterations included G12D/R/V/W, G13D, Q61H, R68S, H95D/Q/R, Y96C, and high-level amplification of the KRASG12C allele. Acquired bypass mechanisms of resistance included MET amplification; activating mutations in NRAS, BRAF, MAP2K1, and RET; oncogenic fusions involving ALK, RET, BRAF, RAF1, and FGFR3; and loss-of-function mutations in NF1 and PTEN. In two of nine patients with lung adenocarcinoma for whom paired tissue-biopsy samples were available, histologic transformation to squamous-cell carcinoma was observed without identification of any other resistance mechanisms. Using an in vitro deep mutational scanning screen, we systematically defined the landscape of KRAS mutations that confer resistance to KRASG12C inhibitors. CONCLUSIONS: Diverse genomic and histologic mechanisms impart resistance to covalent KRASG12C inhibitors, and new therapeutic strategies are required to delay and overcome this drug resistance in patients with cancer. (Funded by Mirati Therapeutics and others; ClinicalTrials.gov number, NCT03785249.).


Assuntos
Acetonitrilas/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Colorretais/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/genética , Neoplasias Pulmonares/tratamento farmacológico , Mutação , Piperazinas/uso terapêutico , Proteínas Proto-Oncogênicas p21(ras)/genética , Pirimidinas/uso terapêutico , Neoplasias do Apêndice/tratamento farmacológico , Neoplasias do Apêndice/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Neoplasias Colorretais/genética , Humanos , Neoplasias Pulmonares/genética , Conformação Proteica , Proteínas Proto-Oncogênicas p21(ras)/antagonistas & inibidores , Proteínas Proto-Oncogênicas p21(ras)/ultraestrutura , Piridinas/uso terapêutico
12.
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
13.
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
14.
Medicine (Baltimore) ; 100(25): e26373, 2021 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-34160411

RESUMO

RATIONALE: Hepatocellular carcinoma (HCC) is the most common liver cancer. The efficacy of the present treatment is disappointing, and the prognosis is poor. Donafenib, a novel multikinase inhibitor, is a new deuterated derivative of sorafenib. It can improve overall survival in patients with advanced HCC, with a favorable safety and tolerability profile over sorafenib. PATIENT CONCERNS: Here, we report the case of a 51-year-old male patient who presented with experienced epigastric discomfort for the prior several days. He had a history of untreated chronic hepatitis B virus infection for >29 years and no other underlying diseases. Based on further investigations, he was diagnosed with advanced HCC and refused surgery. DIAGNOSIS: Based on the patient's performance status, tumor status assessed by computed tomography, liver function, and percutaneous liver biopsy, he was diagnosed with advanced HCC Barcelona Clinic Liver Cancer Stage C. INTERVENTIONS: The patient was administered a 200-mg oral dose of donafenib twice-daily. OUTCOMES: The patient was followed-up from the time of diagnosis. He received donafenib for 31 months, and the progression-free survival time was 31 months (from May 2017 to December 2019); the overall survival time was not reached. The patient reported little abdominal distension with no other obvious discomfort while taking the medication. LESSON: Donafenib showed good efficacy for the treatment of advanced HCC, with mild side effects. Deuterium-containing drugs seem to be a promising avenue for medical innovation.


Assuntos
Carcinoma Hepatocelular/terapia , Guanina/análogos & derivados , Hepatite B Crônica/terapia , Neoplasias Hepáticas/terapia , Piridinas/uso terapêutico , Biópsia , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/virologia , Progressão da Doença , Quimioterapia Combinada/métodos , Guanina/uso terapêutico , Hepatectomia , Hepatite B Crônica/patologia , Hepatite B Crônica/virologia , Humanos , Fígado/diagnóstico por imagem , Fígado/patologia , Fígado/cirurgia , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/virologia , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante/métodos , Tomografia Computadorizada por Raios X , Resultado do Tratamento
16.
Nat Commun ; 12(1): 3962, 2021 06 25.
Artigo em Inglês | MEDLINE | ID: mdl-34172723

RESUMO

Missense mutations in p53 are severely deleterious and occur in over 50% of all human cancers. The majority of these mutations are located in the inherently unstable DNA-binding domain (DBD), many of which destabilize the domain further and expose its aggregation-prone hydrophobic core, prompting self-assembly of mutant p53 into inactive cytosolic amyloid-like aggregates. Screening an oligopyridylamide library, previously shown to inhibit amyloid formation associated with Alzheimer's disease and type II diabetes, identified a tripyridylamide, ADH-6, that abrogates self-assembly of the aggregation-nucleating subdomain of mutant p53 DBD. Moreover, ADH-6 targets and dissociates mutant p53 aggregates in human cancer cells, which restores p53's transcriptional activity, leading to cell cycle arrest and apoptosis. Notably, ADH-6 treatment effectively shrinks xenografts harboring mutant p53, while exhibiting no toxicity to healthy tissue, thereby substantially prolonging survival. This study demonstrates the successful application of a bona fide small-molecule amyloid inhibitor as a potent anticancer agent.


Assuntos
Amiloide/antagonistas & inibidores , Antineoplásicos/farmacologia , Agregação Patológica de Proteínas/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Amidas/química , Amidas/farmacologia , Amidas/uso terapêutico , Amiloide/química , Amiloide/metabolismo , Animais , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Humanos , Camundongos , Mutação , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/genética , Neoplasias Experimentais/metabolismo , Agregação Patológica de Proteínas/tratamento farmacológico , Domínios Proteicos , Piridinas/química , Piridinas/farmacologia , Piridinas/uso terapêutico , Transcrição Genética/efeitos dos fármacos , Proteína Supressora de Tumor p53/química , Proteína Supressora de Tumor p53/genética
17.
Lancet Diabetes Endocrinol ; 9(8): 491-501, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34118198

RESUMO

BACKGROUND: Oncogenic alterations in RET represent important therapeutic targets in thyroid cancer. We aimed to assess the safety and antitumour activity of pralsetinib, a highly potent, selective RET inhibitor, in patients with RET-altered thyroid cancers. METHODS: ARROW, a phase 1/2, open-label study done in 13 countries across 71 sites in community and hospital settings, enrolled patients 18 years or older with RET-altered locally advanced or metastatic solid tumours, including RET-mutant medullary thyroid and RET fusion-positive thyroid cancers, and an Eastern Co-operative Oncology Group performance status of 0-2 (later limited to 0-1 in a protocol amendment). Phase 2 primary endpoints assessed for patients who received 400 mg once-daily oral pralsetinib until disease progression, intolerance, withdrawal of consent, or investigator decision, were overall response rate (Response Evaluation Criteria in Solid Tumours version 1.1; masked independent central review) and safety. Tumour response was assessed for patients with RET-mutant medullary thyroid cancer who had received previous cabozantinib or vandetanib, or both, or were ineligible for standard therapy and patients with previously treated RET fusion-positive thyroid cancer; safety was assessed for all patients with RET-altered thyroid cancer. This ongoing study is registered with clinicaltrials.gov, NCT03037385, and enrolment of patients with RET fusion-positive thyroid cancer was ongoing at the time of this interim analysis. FINDINGS: Between Mar 17, 2017, and May 22, 2020, 122 patients with RET-mutant medullary and 20 with RET fusion-positive thyroid cancers were enrolled. Among patients with baseline measurable disease who received pralsetinib by July 11, 2019 (enrolment cutoff for efficacy analysis), overall response rates were 15 (71%) of 21 (95% CI 48-89) in patients with treatment-naive RET-mutant medullary thyroid cancer and 33 (60%) of 55 (95% CI 46-73) in patients who had previously received cabozantinib or vandetanib, or both, and eight (89%) of nine (95% CI 52-100) in patients with RET fusion-positive thyroid cancer (all responses confirmed for each group). Common (≥10%) grade 3 and above treatment-related adverse events among patients with RET-altered thyroid cancer enrolled by May 22, 2020, were hypertension (24 patients [17%] of 142), neutropenia (19 [13%]), lymphopenia (17 [12%]), and anaemia (14 [10%]). Serious treatment-related adverse events were reported in 21 patients (15%), the most frequent (≥2%) of which was pneumonitis (five patients [4%]). Five patients [4%] discontinued owing to treatment-related events. One (1%) patient died owing to a treatment-related adverse event. INTERPRETATION: Pralsetinib is a new, well-tolerated, potent once-daily oral treatment option for patients with RET-altered thyroid cancer. FUNDING: Blueprint Medicines.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Neuroendócrino/tratamento farmacológico , Mutação , Proteínas Proto-Oncogênicas c-ret/genética , Pirazóis/uso terapêutico , Piridinas/uso terapêutico , Pirimidinas/uso terapêutico , Neoplasias da Glândula Tireoide/tratamento farmacológico , Idoso , Carcinoma Neuroendócrino/genética , Carcinoma Neuroendócrino/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Prognóstico , Taxa de Sobrevida , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/patologia
18.
Rheumatology (Oxford) ; 60(Suppl 2): ii39-ii44, 2021 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-33950224

RESUMO

As our understanding of the pathogenesis of SpA improves, focus has turned to the role janus kinase (JAK)-mediated signal transduction and inhibiting its actions as a therapeutic mechanism. Small molecule inhibitors of JAK exist, with variable selectivity for the different JAK isoforms. Less selective JAK inhibitors have variable efficacy and safety profiles, prompting the investigation of selective JAK1 inhibition. In this review, we summarize the current phase 2 and 3 clinical trial data, evaluating the use of JAK1 selective inhibitors in the treatment of SpA, particularly AS and PsA. Selective JAK1 inhibition offers a promising therapeutic approach, however further longer-term trials are needed to fully establish their efficacy and safety at higher doses, and their use in the greater continuum of SpA.


Assuntos
Artrite Psoriásica/tratamento farmacológico , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Janus Quinase 1/antagonistas & inibidores , Inibidores de Janus Quinases/uso terapêutico , Piridinas/uso terapêutico , Espondilite Anquilosante/tratamento farmacológico , Triazóis/uso terapêutico , Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase III como Assunto , Humanos , Espondiloartropatias/tratamento farmacológico
19.
Rheumatology (Oxford) ; 60(Suppl 2): ii17-ii23, 2021 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-33950225

RESUMO

Upadacitinib and filgotinib, two JAK1 selective drugs have undergone extensive phase III clinical trials in RA and have demonstrated rapid improvements in disease activity, function and patient reported outcomes. Six global phase III randomized controlled clinical trials (SELECT phase III program) evaluated the efficacy and safety of upadacitinib and four clinical phase III trials (the FINCH program) evaluated the efficacy and safety of filgotinib. This article is a critical review of all these studies with focus on the therapeutic efficacy in RA. The aim is to display the data that could allow the approval of these new drugs for the treatment of RA (upadacitinib has been already approved in most of the markets around the world).


Assuntos
Artrite Reumatoide/tratamento farmacológico , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Janus Quinase 1/antagonistas & inibidores , Inibidores de Janus Quinases/uso terapêutico , Piridinas/uso terapêutico , Triazóis/uso terapêutico , Artrite Reumatoide/diagnóstico por imagem , Artrite Reumatoide/fisiopatologia , Ensaios Clínicos Fase III como Assunto , Humanos , Resultado do Tratamento
20.
Rheumatology (Oxford) ; 60(Suppl 2): ii11-ii16, 2021 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-33950228

RESUMO

The first approved Janus kinase (JAK) inhibitors for treatment of RA targeted more than one JAK molecule. Although this brings an advantage of simultaneous blocking of more cytokines involved in RA, it may also carry an increased risk of toxicity. Subsequently, more selective JAK inhibitors were developed with the aim of improving the safety-efficacy profile and to further increase drug maintenance. With this proposal, early phase trials of selective JAK1 inhibitors, namely upadacitinib, filgotinib and itacitinib, were initiated in recent years to identify the efficacy and adverse effects of these agents and to define their potential role in treatment of inflammatory and autoimmune diseases. Early phase (Phase I-II) studies of upadacitinib and filgotinib provided evidence for efficacy and safety of the selective JAK1 inhibitors in refractory populations of RA patients and allowed informed selection of the appropriate dose by balancing the optimal benefit-risk profile for further evaluation in the later successfully performed Phase III trials. Although itacitinib also demonstrated a good efficacy and safety in a Phase II trial in RA patients, it is mainly in development for haematologic and oncologic conditions.


Assuntos
Artrite Reumatoide/tratamento farmacológico , Janus Quinase 1/antagonistas & inibidores , Inibidores de Janus Quinases/uso terapêutico , Acetonitrilas/uso terapêutico , Ensaios Clínicos Fase I como Assunto , Ensaios Clínicos Fase II como Assunto , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Humanos , Pirazóis/uso terapêutico , Piridinas/uso terapêutico , Pirimidinas/uso terapêutico , Pirróis/uso terapêutico , Triazóis/uso terapêutico
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