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1.
Urol Clin North Am ; 47(4): 419-431, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33008493

RESUMO

The management of metastatic renal cell carcinoma (RCC) has evolved rapidly in recent years with several immunotherapy-based combinations of strategies approved as first-line therapies. Targeted strategies, including systemic antiangiogenesis agents and immune checkpoint blockade, form the basis of a therapeutic approach. With rising rates of recurrence after first-line treatment, it is increasingly important to not only adopt a personalized treatment plan with minimal adverse events but also develop predictive biomarkers for response. This review discusses currently available first-line and second-line therapies in RCC and their pivotal data, with specific focus on ongoing clinical trials in the adjuvant setting, including those involving novel agents.


Assuntos
Produtos Biológicos/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Imunoterapia/métodos , Neoplasias Renais/tratamento farmacológico , Carcinoma de Células Renais/mortalidade , Carcinoma de Células Renais/patologia , Carcinoma de Células Renais/cirurgia , Ensaios Clínicos Fase II como Assunto , Terapia Combinada , Quimioterapia Combinada , Feminino , Humanos , Neoplasias Renais/mortalidade , Neoplasias Renais/patologia , Masculino , Invasividade Neoplásica/patologia , Estadiamento de Neoplasias , Nefrectomia/métodos , Prognóstico , Análise de Sobrevida , Resultado do Tratamento , Estados Unidos
2.
Trials ; 21(1): 828, 2020 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-33023671

RESUMO

OBJECTIVES: Primary objectives • To assess the time from randomisation until an improvement within 84 days defined as two points on a seven point ordinal scale or live discharge from the hospital in high-risk patients (group 1 to group 4) with SARS-CoV-2 infection requiring hospital admission by infusion of plasma from subjects after convalescence of SARS-CoV-2 infection or standard of care. Secondary objectives • To assess overall survival, and the overall survival rate at 28 56 and 84 days. • To assess SARS-CoV-2 viral clearance and load as well as antibody titres. • To assess the percentage of patients that required mechanical ventilation. • To assess time from randomisation until discharge. TRIAL DESIGN: Randomised, open-label, multicenter phase II trial, designed to assess the clinical outcome of SARS-CoV-2 disease in high-risk patients (group 1 to group 4) following treatment with anti-SARS-CoV-2 convalescent plasma or standard of care. PARTICIPANTS: High-risk patients >18 years of age hospitalized with SARS-CoV-2 infection in 10-15 university medical centres will be included. High-risk is defined as SARS-CoV-2 positive infection with Oxygen saturation at ≤ 94% at ambient air with additional risk features as categorised in 4 groups: • Group 1, pre-existing or concurrent hematological malignancy and/or active cancer therapy (incl. chemotherapy, radiotherapy, surgery) within the last 24 months or less. • Group 2, chronic immunosuppression not meeting the criteria of group 1. • Group 3, age ≥ 50 - 75 years meeting neither the criteria of group 1 nor group 2 and at least one of these criteria: Lymphopenia < 0.8 x G/l and/or D-dimer > 1µg/mL. • Group 4, age ≥ 75 years meeting neither the criteria of group 1 nor group 2. Observation time for all patients is expected to be at least 3 months after entry into the study. Patients receive convalescent plasma for two days (day 1 and day 2) or standard of care. For patients in the standard arm, cross over is allowed from day 10 in case of not improving or worsening clinical condition. Nose/throat swabs for determination of viral load are collected at day 0 and day 1 (before first CP administration) and subsequently at day 2, 3, 5, 7, 10, 14, 28 or until discharge. Serum for SARS-Cov-2 diagnostic is collected at baseline and subsequently at day 3, 7, 14 and once during the follow-up period (between day 35 and day 84). There is a regular follow-up of 3 months. All discharged patients are followed by regular phone calls. All visits, time points and study assessments are summarized in the Trial Schedule (see full protocol Table 1). All participating trial sites will be supplied with study specific visit worksheets that list all assessments and procedures to be completed at each visit. All findings including clinical and laboratory data are documented by the investigator or an authorized member of the study team in the patient's medical record and in the electronic case report forms (eCRFs). INTERVENTION AND COMPARATOR: This trial will analyze the effects of convalescent plasma from recovered subjects with SARS-CoV-2 antibodies in high-risk patients with SARS-CoV-2 infection. Patients at high risk for a poor outcome due to underlying disease, age or condition as listed above are eligible for enrollment. In addition, eligible patients have a confirmed SARS-CoV-2 infection and O2 saturation ≤ 94% while breathing ambient air. Patients are randomised to receive (experimental arm) or not receive (standard arm) convalescent plasma in two bags (238 - 337 ml plasma each) from different donors (day 1, day 2). A cross over from the standard arm into the experimental arm is possible after day 10 in case of not improving or worsening clinical condition. MAIN OUTCOMES: Primary endpoints: The main purpose of the study is to assess the time from randomisation until an improvement within 84 days defined as two points on a seven-point ordinal scale or live discharge from the hospital in high-risk patients (group 1 to group 4) with SARS-CoV-2 infection requiring hospital admission by infusion of plasma from subjects after convalescence of a SARS-CoV-2 infection or standard of care. Secondary endpoints: • Overall survival, defined as the time from randomisation until death from any cause 28-day, 56-day and 84-day overall survival rates. • SARS-CoV-2 viral clearance and load as well as antibody titres. • Requirement mechanical ventilation at any time during hospital stay (yes/no). • Time until discharge from randomisation. • Viral load, changes in antibody titers and cytokine profiles are analysed in an exploratory manner using paired non-parametric tests (before - after treatment). RANDOMISATION: Upon confirmation of eligibility (patients must meet all inclusion criteria and must not meet exclusion criteria described in section 5.3 and 5.4 of the full protocol), the clinical site must contact a centralized internet randomization system ( https://randomizer.at/ ). Patients are randomized using block randomisation to one of the two arms, experimental arm or standard arm, in a 1:1 ratio considering a stratification according to the 4 risk groups (see Participants). BLINDING (MASKING): The study is open-label, no blinding will be performed. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): A total number of 174 patients is required for the entire trial, n=87 per group. TRIAL STATUS: Protocol version 1.2 dated 09/07/2020. A recruitment period of approximately 9 months and an overall study duration of approximately 12 months is anticipated. Recruitment of patients starts in the third quarter of 2020. The study duration of an individual patient is planned to be 3 months. After finishing all study-relevant procedures, therapy, and follow-up period, the patient is followed in terms of routine care and treated if necessary. Total trial duration: 18 months Duration of the clinical phase: 12 months First patient first visit (FPFV): 3rd Quarter 2020 Last patient first visit (LPFV): 2nd Quarter 2021 Last patient last visit (LPLV): 3rd Quarter 2021 Trial Report completed: 4th Quarter 2021 TRIAL REGISTRATION: EudraCT Number: 2020-001632-10, https://www.clinicaltrialsregister.eu/ctr-search/trial/2020-001632-10/DE , registered on 04/04/2020. FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol. The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2). The eCRF is attached (Additional file 3).


Assuntos
Anticorpos Antivirais/sangue , Betacoronavirus , Infecções por Coronavirus , Pandemias , Plasma/imunologia , Pneumonia Viral , Idoso , Betacoronavirus/imunologia , Betacoronavirus/isolamento & purificação , Ensaios Clínicos Fase II como Assunto , Convalescença , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/terapia , Feminino , Humanos , Imunização Passiva/métodos , Masculino , Pessoa de Meia-Idade , Monitorização Fisiológica/métodos , Estudos Multicêntricos como Assunto , Pneumonia Viral/diagnóstico , Pneumonia Viral/imunologia , Pneumonia Viral/terapia , Ensaios Clínicos Controlados Aleatórios como Assunto , Risco Ajustado , Índice de Gravidade de Doença
3.
Respir Res ; 21(1): 265, 2020 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-33050900

RESUMO

BACKGROUND: Patients with severe, uncontrolled asthma, particularly those with a non-eosinophilic phenotype, have a great unmet need for new treatments that act on a broad range of inflammatory pathways in the airway. Tezepelumab is a human monoclonal antibody that blocks the activity of thymic stromal lymphopoietin, an epithelial cytokine. In the PATHWAY phase 2b study (NCT02054130), tezepelumab reduced exacerbations by up to 71% in adults with severe, uncontrolled asthma, irrespective of baseline eosinophilic inflammatory status. This article reports the design and objectives of the phase 2 CASCADE study. METHODS: CASCADE is an ongoing exploratory, phase 2, randomized, double-blind, placebo-controlled, parallel-group study aiming to assess the anti-inflammatory effects of tezepelumab 210 mg administered subcutaneously every 4 weeks for 28 weeks in adults aged 18-75 years with uncontrolled, moderate-to-severe asthma. The primary endpoint is the change from baseline to week 28 in airway submucosal inflammatory cells (eosinophils, neutrophils, T cells and mast cells) from bronchoscopic biopsies. Epithelial molecular phenotyping, comprising the three-gene-mean technique, will be used to assess participants' type 2 (T2) status to enable evaluation of the anti-inflammatory effect of tezepelumab across the continuum of T2 activation. Other exploratory analyses include assessments of the impact of tezepelumab on airway remodelling, including reticular basement membrane thickening and airway epithelial integrity. At the onset of the COVID-19 pandemic, the protocol was amended to address the possibility that site visits would be limited. The amendment allowed for: at-home dosing of study drug by a healthcare professional, extension of the treatment period by up to 6 months so patients are able to attend an onsite visit to undergo the end-of-treatment bronchoscopy, and replacement of final follow-up visits with a virtual or telephone visit. DISCUSSION: CASCADE aims to determine the mechanisms by which tezepelumab improves clinical asthma outcomes by evaluating the effect of tezepelumab on airway inflammatory cells and remodelling in patients with moderate-to-severe, uncontrolled asthma. An important aspect of this study is the evaluation of the anti-inflammatory effect of tezepelumab across patients with differing levels of eosinophilic and T2 inflammation. TRIAL REGISTRATION: NCT03688074 (ClinicalTrials.gov). Registered 28 September 2018.


Assuntos
Antiasmáticos/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Asma/tratamento farmacológico , Adolescente , Adulto , Idoso , Antiasmáticos/efeitos adversos , Anti-Inflamatórios/efeitos adversos , Anticorpos Monoclonais Humanizados/efeitos adversos , Asma/diagnóstico , Asma/imunologia , Ensaios Clínicos Fase II como Assunto , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Multicêntricos como Assunto , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento , Adulto Jovem
4.
Med Hypotheses ; 143: 110110, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33017904

RESUMO

Current formulations and dose regimens of hydroxychloroquine (HCQ) put patients at risk of harm. An analysis of clinical trials registered on ClinicalTrials.gov revealed that this may continue as many studies combine HCQ with agents that prolong the QT interval. Further, almost all of the trials registered do not consider dosage adjustment in the elderly, a patient population most likely to require HCQ treatment. Here we describe an inhaled formulation of HCQ which has passed safety studies in clinical trials for the treatment of asthma and discuss how this approach may reduce side-effects and improve efficacy. As this simple formulation progressed to phase II studies, safety data can be used to immediately enable phase II trials in COVID-19.


Assuntos
Infecções por Coronavirus/tratamento farmacológico , Hidroxicloroquina/administração & dosagem , Pulmão/efeitos dos fármacos , Pneumonia Viral/tratamento farmacológico , Administração por Inalação , Adolescente , Adulto , Idoso , Asma/tratamento farmacológico , Betacoronavirus , Ensaios Clínicos Fase I como Assunto , Ensaios Clínicos Fase II como Assunto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pandemias , Segurança do Paciente , Resultado do Tratamento , Adulto Jovem
5.
Trials ; 21(1): 758, 2020 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-32883328

RESUMO

OBJECTIVES: Tocilizumab is a humanized monoclonal antibody which targets and inhibits interleukin-6 (IL-6) and has demonstrated efficacy in treating diseases associated with hyper-inflammation. Data are suggestive of tocilizumab as a potential treatment for patients with COVID-19 infection. The aim of this study is to determine the safety and efficacy of standard dose versus low dose tocilizumab in adults with severe, non-critical, PCR-confirmed COVID-19 infection with evidence of progressive decline in respiratory function and evolving systemic inflammation on time to intubation, non-invasive ventilation and/or all-cause mortality. TRIAL DESIGN: This trial is a phase 2, open label, two-stage, multicentre, randomised trial. PARTICIPANTS: Adult subjects with severe, non-critical, PCR-confirmed COVID-19 infection with evidence of progressive decline in respiratory function and evolving systemic inflammation requiring admission to hospital at St. Vincent's University Hospital and Mater Misericordiae University Hospital, Dublin, Ireland. Inclusion criteria Aged 18 years or older. Confirmed SARS-CoV2 infection (as defined by positive PCR). Evidence of hyper inflammatory state as evidenced by at least three of the following: Documented temperature >38°C in the past 48 hours, IL6 >40 pg/ml, or in its absence D-dimer >1.5 µgFEU /ml, Elevated CRP (>100mg/L) and/or a three-fold increase since presentation, Elevated ferritin X5 ULN, Elevated LDH (above the ULN), Elevated fibrinogen (above the ULN). Pulmonary infiltrates on chest imaging. Moderate to severe respiratory failure as defined by PaO2/FiO2≤300mmHg. INTERVENTION AND COMPARATOR: Intervention for participants in this trial is SOC plus Tocilizumab compared to SOC alone (comparator). For Stage 1, following randomisation, subjects will receive either (Arm 1) SOC alone or (Arm 2) SOC plus Tocilizumab (standard single dose - 8mg/kg, infused over 60 minutes. Once stage 1 has fully recruited, subsequent participants will be enrolled directly into Stage 2 and receive either (Arm 1) SOC plus Tocilizumab (standard single dose - 8mg/kg, infused over 60 minutes or (Arm 2) SOC plus Tocilizumab (standard single dose - 4mg/kg, infused over 60 minutes). MAIN OUTCOMES: The primary endpoint for this study is the time to a composite primary endpoint of progression to intubation and ventilation, non-invasive ventilation or death within 28 days post randomisation. RANDOMISATION: Eligible patients will be randomised (1:1) using a central register. Randomisation will be performed through an interactive, web-based electronic data capturing database. In stage 1, eligible participants will be randomised (1:1) to (Arm 1) SOC alone or to (Arm 2) SOC with single dose (8mg/kg, maximum 800mg) intravenous tocilizumab infused over 60 minutes. In stage 2, eligible participants will be randomised (1:1) to receive either (Arm 1) single, standard dose (8mg/kg, maximum 800mg) intravenous tocilizumab infused over 60 minutes or (Arm 2) reduced dose (4mg/kg, maximum 800mg) intravenous tocilizumab infused over 60 minutes. BLINDING: This study is open label. The study will not be blinded to investigators, subjects, or medical or nursing staff. The trial statistician will be blinded for data analysis and will be kept unaware of treatment group assignments. To facilitate this, the randomisation schedule will be drawn up by an independent statistician and objective criteria were defined for the primary outcome to minimize potential bias. NUMBERS TO BE RANDOMISED: In stage 1, 90 subjects will be randomised 1:1, 45 to SOC and 45 subjects to SOC plus Tocilizumab (8mg/kg, infused over 60 minutes). In stage 2, sample size calculation for the dose evaluation stage will use data generated from stage 1 using the same primary endpoint as in stage 1. TRIAL STATUS: The COVIRL002 trial (Protocol version 1.4, 13th May 2020) commenced in May 2020 at St. Vincent's University Hospital and Mater Misericordiae University Hospital, Dublin, Ireland. Recruitment is proceeding with the aim to achieve the target sample size on or before April 2021. TRIAL REGISTRATION: COVIRL002 was registered 25 June 2020 under EudraCT number: 2020-001767-86 and Protocol identification: UCDCRC/20/02. FULL PROTOCOL: The full protocol for COVIRL002 is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol. The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2).


Assuntos
Anti-Inflamatórios/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Anti-Inflamatórios/efeitos adversos , Anticorpos Monoclonais Humanizados/efeitos adversos , Betacoronavirus/patogenicidade , Ensaios Clínicos Fase II como Assunto , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/mortalidade , Infecções por Coronavirus/virologia , Progressão da Doença , Interações entre Hospedeiro e Microrganismos , Humanos , Intubação Intratraqueal , Irlanda , Estudos Multicêntricos como Assunto , Pandemias , Pneumonia Viral/diagnóstico , Pneumonia Viral/mortalidade , Pneumonia Viral/virologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Respiração Artificial , Índice de Gravidade de Doença , Fatores de Tempo , Resultado do Tratamento
6.
Trials ; 21(1): 766, 2020 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-32891160

RESUMO

OBJECTIVES: To investigate the potential efficacy of Acacia Senegal extract Gum Arabic (GA) supplementation as immunomodulatory and anti-inflammatory dietary intervention among newly diagnosed COVID 19 Sudanese patients. To study the effect of GA on the level of cytokines, TNFα, IL8, IL6 IL10, CRP and the viral load. Secondary outcomes will be the effect of GA oral intake on mortality rate and days of hospital admission. TRIAL DESIGN: Quadruple blind, randomized placebo-controlled clinical trial Phase II & III. Prospective, two-arm, parallel-group, randomised (1:1 allocation ratio) superiority trial of oral GA among seropositive COVID-19 patients. PARTICIPANTS: Inclusion criteria: COVID-19 infected (newly diagnosed) as proved by real-time PCR within 72 hours of PCR. Age 8-90 years Both genders Exclusion criteria: Intubated patients on parenteral treatment Allergy to Gum Arabic The study will be conducted in COVID Isolation Centres and Soba University Hospital Khartoum State Sudan. INTERVENTION AND COMPARATOR: Experimental: Intervention Group This arm will receive 100% natural Gum Arabic provided in a powder form in 30-grams-dose once daily for four weeks Placebo Comparator: Control group: This group will be provided with pectin powder provided as one-gram-dose once daily for four weeks Both GA and placebo will be in addition to standard care treatment based on local clinical guidelines. MAIN OUTCOMES: Mean change from baseline score of Immune Response to end of the trial. Changes of the level of Tumor Necrosis Factor (TNFα), interleukin IL8, IL6, and IL10 from the baseline values (Four weeks from the start of randomization). Mortality rate: The percentage of deaths among COVID 19 patients received Gum Arabic compared to placebo (Four weeks from the start of randomization]). RANDOMISATION: Randomization (1:1 allocation ratio) and will be conducted using a sequence of computer-generated random numbers by an independent individual. Each participating centre will be assigned a special code generated by the computer. The randomization will be kept by the PI and a research assistant. BLINDING (MASKING): Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor) NUMBERS TO BE RANDOMISED (SAMPLE SIZE): 110 eligible patients will be randomly assigned to either GA (n=55) or placebo (n=55) groups. TRIAL STATUS: Protocol Version no 2, 30th June 2020. Recruitment will start on 15th September 2020. The intended completion date is 15th January 2021. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04381871 . Date of trial registration: 11 May 2020. FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.


Assuntos
Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Goma Arábica/uso terapêutico , Fatores Imunológicos/uso terapêutico , Pneumonia Viral/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Betacoronavirus/imunologia , Betacoronavirus/patogenicidade , Criança , Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase III como Assunto , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Feminino , Goma Arábica/efeitos adversos , Interações entre Hospedeiro e Microrganismos , Humanos , Fatores Imunológicos/efeitos adversos , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/diagnóstico , Pneumonia Viral/imunologia , Pneumonia Viral/virologia , Estudos Prospectivos , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
7.
Virol J ; 17(1): 141, 2020 09 24.
Artigo em Inglês | MEDLINE | ID: mdl-32972430

RESUMO

BACKGROUND: The COVID-19 causing coronavirus is an enveloped RNA virus that utilizes an enzyme RNA dependent RNA polymerase for its replication. Favipiravir (FVP) triphosphate, a purine nucleoside analog, inhibits that enzyme. We have conducted this systematic review and meta-analysis on efficacy and safety of the drug FVP as a treatment for COVID-19. METHODS: Databases like Pubmed, Pubmed Central, Scopus, Embase, Google Scholar, preprint sites, and clinicaltirals.gov were searched. The studies with the standard of care (SOC) and FVP as a treatment drug were considered as the treatment group and the SOC with other antivirals and supportive care as the control group. Quantitative synthesis was done using RevMan 5.4. Clinical improvement, negative conversion of reverse transcription-polymerase chain reaction (RT-PCR), adverse effects, and oxygen requirements were studied. RESULTS: We identified a total of 1798 studies after searching the electronic databases. Nine in the qualitative studies and four studies in the quantitative synthesis met the criteria. There was a significant clinical improvement in the FVP group on the 14th day compared to the control group (RR 1.29, 1.08-1.54). Clinical deterioration rates were less likely in the FVP group though statistically not significant (OR 0.59, 95% CI 0.30-1.14) at the endpoint of study (7-15 days). The meta-analysis showed no significant differences between the two groups on viral clearance (day 14: RR 1.06, 95% CI 0.84-1.33), non-invasive ventilation or oxygen requirement (OR 0.76, 95% CI 0.42-1.39), and adverse effects (OR 0.69, 0.13-3.57). There are 31 randomized controlled trials (RCTs) registered in different parts of the world focusing FVP for COVID-19 treatment. CONCLUSION: There is a significant clinical and radiological improvement following treatment with FVP in comparison to the standard of care with no significant differences on viral clearance, oxygen support requirement and side effect profiles.


Assuntos
Amidas/uso terapêutico , Antivirais/uso terapêutico , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Pirazinas/uso terapêutico , Amidas/efeitos adversos , Antivirais/efeitos adversos , Betacoronavirus/enzimologia , Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase III como Assunto , Infecções por Coronavirus/virologia , RNA Polimerases Dirigidas por DNA/antagonistas & inibidores , Bases de Dados Factuais , Inibidores Enzimáticos/uso terapêutico , Humanos , Pandemias , Pneumonia Viral/virologia , Pirazinas/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Padrão de Cuidado , Resultado do Tratamento
8.
BMC Med Res Methodol ; 20(1): 220, 2020 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-32867708

RESUMO

BACKGROUND: Because of unknown features of the COVID-19 and the complexity of the population affected, standard clinical trial designs on treatments may not be optimal in such patients. We propose two independent clinical trials designs based on careful grouping of patient and outcome measures. METHODS: Using the World Health Organization ordinal scale on patient status, we classify treatable patients (Stages 3-7) into two risk groups. Patients in Stages 3, 4 and 5 are categorized as the intermediate-risk group, while patients in Stages 6 and 7 are categorized as the high-risk group. To ensure that an intervention, if deemed efficacious, is promptly made available to vulnerable patients, we propose a group sequential design incorporating four factors stratification, two interim analyses, and a toxicity monitoring rule for the intermediate-risk group. The primary response variable (binary variable) is based on the proportion of patients discharged from hospital by the 15th day. The goal is to detect a significant improvement in this response rate. For the high-risk group, we propose a group sequential design incorporating three factors stratification, and two interim analyses, with no toxicity monitoring. The primary response variable for this design is 30 day mortality, with the goal of detecting a meaningful reduction in mortality rate. RESULTS: Required sample size and toxicity boundaries are calculated for each scenario. Sample size requirements for designs with interim analyses are marginally greater than ones without. In addition, for both the intermediate-risk group and the high-risk group, the required sample size with two interim analyses is almost identical to analyses with just one interim analysis. CONCLUSIONS: We recommend using a binary outcome with composite endpoints for patients in Stage 3, 4 or 5 with a power of 90% to detect an improvement of 20% in the response rate, and a 30 day mortality rate outcome for those in Stage 6 or 7 with a power of 90% to detect 15% (effect size) reduction in mortality rate. For the intermediate-risk group, two interim analyses for efficacy evaluation along with toxicity monitoring are encouraged. For the high-risk group, two interim analyses without toxicity monitoring is advised.


Assuntos
Betacoronavirus , Infecções por Coronavirus/terapia , Interpretação Estatística de Dados , Pneumonia Viral/terapia , Projetos de Pesquisa , Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase III como Assunto , Humanos , Avaliação de Resultados em Cuidados de Saúde , Pandemias
9.
Cochrane Database Syst Rev ; 9: CD004448, 2020 09 25.
Artigo em Inglês | MEDLINE | ID: mdl-32977351

RESUMO

BACKGROUND: Sickle cell disease, a common recessively inherited haemoglobin disorder, affects people from sub-Saharan Africa, the Middle East, Mediterranean basin, Indian subcontinent, Caribbean and South America. It is associated with complications and a reduced life expectancy. Phytomedicines (medicine derived from plants in their original state) encompass many of the plant remedies from traditional healers which the populations most affected would encounter. Laboratory research and limited clinical trials have suggested positive effects of phytomedicines both in vivo and in vitro. However, there has been little systematic appraisal of their benefits. This is an updated version of a previously published Cochrane Review. OBJECTIVES: To assess the benefits and risks of phytomedicines in people with sickle cell disease of all types, of any age, in any setting. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Haemoglobinopathies Trials Register, the International Standard Randomised Controlled Trial Number Register (ISRCTN), the Allied and Complimentary Medicine Database (AMED), ClinicalTrials.gov and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP). Dates of most recent searches: Cochrane Cystic Fibrosis and Genetic Disorders Haemoglobinopathies Trials Register: 17 March 2020; ISRCTN: 19 April 2020; AMED: 18 May 2020; ClinicalTrials.gov: 24 April 2020; and the WHO ICTRP: 27 July 2017. SELECTION CRITERIA: Randomised or quasi-randomised trials with participants of all ages with sickle cell disease, in all settings, comparing the administration of phytomedicines, by any mode to placebo or conventional treatment, including blood transfusion and hydroxyurea. DATA COLLECTION AND ANALYSIS: Both authors independently assessed trial quality and extracted data. MAIN RESULTS: Three trials (212 participants) of three phytomedicines: Niprisan® (also known as Nicosan®), Ciklavit® and a powdered extract of Pfaffia paniculata were included. The Phase IIB (pivotal) trial suggests that Niprisan® may be effective in reducing episodes of severe painful sickle cell disease crisis over a six-month period (low-quality evidence). It did not appear to affect the risk of severe complications or the level of anaemia (low-quality evidence). The single trial of Cajanus cajan (Ciklavit®) reported a possible benefit to individuals with painful crises, and a possible adverse effect (non-significant) on the level of anaemia (low-quality evidence). We are uncertain of the effect of Pfaffia paniculata on the laboratory parameters and symptoms of SCD (very low-quality of evidence). No adverse effects were reported with Niprisan® and Pfaffia paniculata (low- to very low-quality evidence). AUTHORS' CONCLUSIONS: While Niprisan® appeared to be safe and effective in reducing severe painful crises over a six-month follow-up period, further trials are required to assess its role in managing people with SCD and the results of its multicentre trials are awaited. Currently, no conclusions can be made regarding the efficacy of Ciklavit® and the powdered root extract of Pfaffia paniculata in managing SCD. Based on the published results for Niprisan® and in view of the limitations in data collection and analysis of the three trials, phytomedicines may have a potential beneficial effect in reducing painful crises in SCD. This needs to be further validated in future trials. More trials with improved study design and data collection are required on the safety and efficacy of phytomedicines used in managing SCD.


Assuntos
Anemia Falciforme/tratamento farmacológico , Antidrepanocíticos/uso terapêutico , Fitoterapia , Extratos Vegetais/uso terapêutico , Adolescente , Adulto , Amaranthaceae/química , Anemia/induzido quimicamente , Anemia Falciforme/sangue , Antidrepanocíticos/efeitos adversos , Criança , Pré-Escolar , Ensaios Clínicos Fase II como Assunto , Feminino , Humanos , Lactente , Masculino , Fitoterapia/efeitos adversos , Extratos Vegetais/efeitos adversos , Raízes de Plantas/química , Ensaios Clínicos Controlados Aleatórios como Assunto
10.
Trials ; 21(1): 794, 2020 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-32938496

RESUMO

OBJECTIVES: In some patients, acute, life-threatening respiratory injury produced by viruses such as SARS-CoV and other viral pneumonia are associated with an over-exuberant cytokine release. Elevated levels of blood IL-6 had been identified as a one of the risk factors associated with severe COVID-19 disease. Anti-IL6 inhibitors are among the therapeutic armamentarium for preventing the fatal consequences of acute respiratory and multi organ failure in around 20% of the COVID-19 infected patients. At present, their use is prioritized to patients with severe interstitial pneumonia (Brescia-COVID Scale-COVID 2-3) with hyperinflammation as determined by the presence of elevated IL6 and/or d-dimer, or progressive d-dimer increase, in patients who otherwise are subsidiary to ICU admission. However, many uncertainties remain on the actual role of anti-IL6 inhibitors in this setting, and whether current use and timing is the right one. There is the hypothesis that the use of anti-IL6 inhibitors at an earlier state during the hyperinflammatory syndrome would be beneficial and may avoid progressing to ARDS. On the other hand, the standard of care has changed and nowadays the use of corticosteroids has become part of the SOC in the treatment of COVID-19 pneumonia. Our limited experience suggests that better treatment outcomes can be achieved when combining IL6-inhibitors (e.g. sarilumab) with corticosteroids. The aim of the present study is to evaluate if an earlier therapeutic intervention with sarilumab plus SOC (including corticosteroids) may be more effective than current standard of care alone, in preventing progression to respiratory failure in COVID-19 infected patients with interstitial pneumonia. This study will also provide supportive evidence to that provided by currently ongoing studies on the efficacy and safety of sarilumab in this clinical context. TRIAL DESIGN: A phase two multi-center randomised controlled trial (RCT) with two parallel arms (1:1 ratio). PARTICIPANTS: They will be hospitalized patients, of at least 18 years of age, with severe COVID-19 who have positive RT-PCR test and have radiographic evidence of pulmonary infiltrates by imaging or rales/crackles on exam and SpO2 ≤ 94% on room air that requires supplemental oxygen. Patients must present elevation of inflammatory parameters (IL-6 > 40 pg/mL or d-dimer >1.0 mcg/ml) or, alternatively, progressive worsening in at least two of these inflammatory parameters in the prior 24-48h: CRP, LDH, serum ferritin, lymphopenia, or d-dimer. EXCLUSION CRITERIA: high oxygen requirements (including face mask with reservoir, non-invasive mechanical ventilation or high flow nasal cannula, or mechanical ventilation), admission to ICU, pregnancy or lactation, allergy or hypersensitivity to sarilumab or corticoesteroids, immunosuppressive antibody therapy within the past 5 months, AST/ALT values > 10 x ULN, neutropenia (< 0.5 x 109/L), severe thrombocytopenia (< 50 x 109/L), sepsis caused by an alternative pathogen, diverticulitis with risk of perforation or ongoing infectious dermatitis. The study will be conducted in several hospitals in Spain. INTERVENTION AND COMPARATOR: Patients randomised to the experimental arm will receive sarilumab + methylprednisolone plus SOC for COVID-19. Patients included in the control arm will receive methylprednisolone plus SOC for COVID-19. Corticosteroids will be given to all patients at a 1mg/kg/d of methylprednisolone for at least 3 days. Clinical follow-up visits will be performed at 3, 5, and 15 days after treatment randomization. Patients in the control group (SOC group without sarilumab) progressing to Brescia- COVID 2-3 plus inflammatory markers, will be given the option to be rescued with sarilumab at the same doses and, in that case, be included in an open-label phase and be followed up for additional weeks (with visits at 3, 7 and 15 days after sarilumab rescue administration). Patients randomly assigned to sarilumab therapy at baseline progressing to Brescia-COVID 2-3 will be rescued according to local clinical practice protocols. A final follow-up visit will be conducted for all patients at day 29 from randomization, regardless of initial treatment assignment. MAIN OUTCOMES: Primary end point is the proportion of patients progressing to either severe respiratory failure (Brescia-COVID ≥2), ICU admission, or death. RANDOMIZATION: Randomization codes were produced by means of the PROC PLAN of the SAS system, with a 1:1 assignment ratio, stratifying by centre and using blocks multiple of 2 elements. The randomization schedule will be managed through the eCRF in a concealed manner. BLINDING (MASKING): All study drugs will be administered as open label. No blinding methods will be used in this trial. NUMBERS TO BE RANDOMISED (SIMPLE SIZE): The target sample size will be 200 COVID-19 patients, who will be allocated randomly to control arm (100) and treatment arm (100). TRIAL STATUS: Protocol Code: SARTRE Protocol Date: May 05th 2020. Version: 2.0 The study has been approved by the Spanish Competent Authority (AEMPS) as a low intervention clinical trial. Start of recruitment: August, 2020 End of recruitment: May, 2021 TRIAL REGISTRATION: Identifier: EudraCT Number: 2020-002037-15 ; Registration date: 26 May 2020. FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this letter serves as a summary of the key elements of the full protocol. The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2).


Assuntos
Anticorpos Monoclonais Humanizados , Betacoronavirus , Infecções por Coronavirus , Síndrome da Liberação de Citocina/prevenção & controle , Pandemias , Pneumonia Viral , Adulto , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/efeitos adversos , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/isolamento & purificação , Ensaios Clínicos Fase II como Assunto , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/fisiopatologia , Síndrome da Liberação de Citocina/imunologia , Feminino , Humanos , Masculino , Pneumonia Viral/diagnóstico , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/etiologia , Pneumonia Viral/imunologia , Pneumonia Viral/fisiopatologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Receptores de Interleucina-6/antagonistas & inibidores , Resultado do Tratamento
11.
Cancer Treat Rev ; 89: 102066, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32769038

RESUMO

Metronomic chemotherapy (M-CT) is defined as dose dense administration of chemotherapy at lower doses than maximum tolerated dose but at shorter free intervals, to obtain a near continuous exposure of cancer cells to those potentially effective drugs. M-CT is a useful strategy to obtain response, overcome resistance and reduce side effects, with low costs. This review will focus on the use of M-CT in advanced breast cancer (ABC). Cytostatic and cytotoxic effect on cancer cells, the anti-angiogenic and the immunomodulatory effects are its main mechanisms of actions. Many clinical trials proved the efficacy and tolerability of different monotherapies and combinations of chemotherapeutic agents administered in metronomic doses and frequencies in ABC. M-CT is a reasonable option for second and later lines of chemotherapy in metastatic breast cancer including those with prior anthracycline or taxane exposure, older patients and patients with comorbidities, and even as first-line in certain groups of patients. The acceptable efficacy and low toxicity of oral metronomic chemotherapy makes it a reasonable option during COVID-19 pandemic as well as in the post-COVID era which is projected to last for some time.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/virologia , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/prevenção & controle , Pandemias/prevenção & controle , Pneumonia Viral/epidemiologia , Pneumonia Viral/prevenção & controle , Administração Metronômica , Neoplasias da Mama/patologia , Ensaios Clínicos Fase II como Assunto , Infecções por Coronavirus/transmissão , Feminino , Humanos , Metástase Neoplásica , Pneumonia Viral/transmissão , Ensaios Clínicos Controlados Aleatórios como Assunto
12.
Cancer Treat Rev ; 89: 102072, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32769039

RESUMO

BACKGROUND: Patients with advanced urothelial carcinoma (UC) have poor outcomes, with 5-year survival rates of <5% for those with metastatic, stage IV disease. We have reviewed current treatment paradigms and emerging treatment options for these patients. METHODS: The websites of seven national or international organizations were searched for metastatic UC treatment guidelines. Systematic literature reviews were conducted to identify evidence from randomized controlled trials (RCTs) of chemotherapy for patients with previously untreated, unresectable, stage IV UC. Searches included congress databases and articles published between 1990 and 2018. In order to align with the latest treatment paradigms in first-line advanced UC, a focused literature search was conducted to identify evidence supporting immuno-oncology (IO) agents. RESULTS: For advanced UC, guidelines universally recommend cisplatin-based chemotherapy as first-line treatment for eligible patients and carboplatin-based regimens for those unfit to receive cisplatin. Despite the evaluation of a number of different cytotoxic regimens over the years, including triplet combinations, survival outcomes have not improved markedly with chemotherapy. Median overall survival with standard of care chemotherapy is ~13 months. Based on the results of single-arm, phase II studies, recent treatment guidelines have included atezolizumab (anti-PD-L1) and pembrolizumab (anti-PD-1) as first-line options for cisplatin-ineligible patients whose tumors express high levels of PD-L1. However, emerging evidence from RCTs of IO agents, including both cisplatin-eligible and cisplatin-ineligible patients, suggest that survival times exceeding 20 months are possible. CONCLUSIONS: After having reached a plateau with chemotherapy, the treatment landscape for advanced UC is evolving. Survival outcomes for patients with advanced UC are improving with treatment modalities involving IO agents.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células de Transição/tratamento farmacológico , Neoplasias da Bexiga Urinária/tratamento farmacológico , Carcinoma de Células de Transição/patologia , Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase III como Assunto , Humanos , Metástase Neoplásica , Estadiamento de Neoplasias , Guias de Prática Clínica como Assunto , Ensaios Clínicos Controlados Aleatórios como Assunto , Neoplasias da Bexiga Urinária/patologia
13.
Cancer Treat Rev ; 89: 102085, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32771858

RESUMO

Immune checkpoint inhibitors (ICIs) represent one of the main steps forward for the treatment of advanced or metastatic non-small-cell lung cancer (NSCLC), without oncogenic driver alterations. Despite this recent progress, only a minority of patients achieve a broad and durable benefit and another proportion report poor survival and sometimes fast disease progression, confirming the need to optimise the patient's selection. To date, several issues are unsolved about how to personalise the immunotherapy treatment for individual patients. In this review, analysing data from pivotal randomised clinical trials (RCTs), we discuss patient baseline clinical and demographic features, including sex, age, ECOG performance status, smoking habit and specific site of metastases (liver, bone and brain) that may influence the efficacy outcomes in patients treated with ICIs. The high performance of the ICIs blurred the vision on different efficacy-limiting factors, which require extensive evaluation to improve the understanding ofthe tumour-specificimmune response, in which clinical drivers could be useful for better patient stratification.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Antineoplásicos Imunológicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/imunologia , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase III como Assunto , Humanos , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/mortalidade , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Ensaios Clínicos Controlados Aleatórios como Assunto
14.
PLoS One ; 15(8): e0237175, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32790757

RESUMO

Patients' vitamin intake is often not documented and is therefore not considered sufficiently in studies of prescribed medication in patients with amyotrophic lateral sclerosis (ALS). We aimed to determine the prevalence of vitamin use by participants in ALS clinical trials. Data about demographics, disease severity (ALS Functional Rating Scale) and concomitant medication were obtained from the Pooled Resource Open-Access ALS Clinical Trials Database, which contains records from more than 6000 ALS patients who participated in 23 phase II/III clinical trials. Information about vitamin intake for all study subjects was coded into major categories. Clinical data of vitamin users and nonusers were compared, and regression analysis was used to explore the associations among clinical parameters, vitamin use and two measures of disease progression. From the 40.996 available medication records from 6274 subjects, 7338 (17.9%) concerned vitamins. One or more vitamins were used by 3331 subjects (53.1%). Most common was vitamin E, vitamin C and multivitamins. Patients who did and did not take vitamins did not differ in terms of disease progression and ALS Functional Rating Scale score. Patients who took vitamins were younger, were more often female, had a shorter time between onset and diagnosis, had shorter disease duration and more frequently had limb-onset types. Disease progression rate and disease aggressiveness were not associated with vitamin use. Despite unclear evidence, the use of vitamins in ALS is common. However, rapid progression was not observed to be associated with vitamin use.


Assuntos
Esclerose Amiotrófica Lateral/tratamento farmacológico , Uso de Medicamentos/estatística & dados numéricos , Vitaminas/administração & dosagem , Adulto , Idoso , Esclerose Amiotrófica Lateral/epidemiologia , Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase III como Assunto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Vitaminas/uso terapêutico
15.
Ann Hematol ; 99(10): 2357-2366, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32808106

RESUMO

Rituximab monotherapy is widely used for follicular lymphoma. However, there are no established predictors for response or response duration. We analyzed the long-term prognostic relevance of pre-treatment absolute blood counts of lymphocytes with subsets and monocytes in 265 follicular lymphoma patients, uniformly treated with rituximab without chemotherapy, in two Nordic Lymphoma Group trials. There were 265 previously untreated, stage II-IV follicular lymphoma patients with a median follow-up of over 10 years. Absolute B cell counts ≥ median (0.09 × 109/L) were an independent predictor for shorter time to next treatment or death (multivariable analysis P = 0.010). In univariate analysis, absolute monocyte counts ≥ median (0.5 × 109/L) did not correlate with time to next treatment or death, but with inferior overall survival (P = 0.034). Absolute T cell or T cell subset counts were not predictive for outcome. High absolute B cell counts, possibly reflecting circulating lymphoma cells, have an unfavorable impact on time to next treatment or death in patients treated with rituximab without chemotherapy.


Assuntos
Antineoplásicos/uso terapêutico , Linfócitos B , Imunossupressores/uso terapêutico , Contagem de Linfócitos , Linfoma Folicular/tratamento farmacológico , Rituximab/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ensaios Clínicos Fase II como Assunto/estatística & dados numéricos , Ensaios Clínicos Fase III como Assunto/estatística & dados numéricos , Conjuntos de Dados como Assunto , Feminino , Seguimentos , Humanos , Interferon alfa-2/administração & dosagem , Estimativa de Kaplan-Meier , Subpopulações de Linfócitos , Linfoma Folicular/sangue , Masculino , Pessoa de Meia-Idade , Monócitos , Estudos Multicêntricos como Assunto/estatística & dados numéricos , Prognóstico , Ensaios Clínicos Controlados Aleatórios como Assunto/estatística & dados numéricos , Rituximab/administração & dosagem , Adulto Jovem
16.
PLoS One ; 15(8): e0238021, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32841306

RESUMO

Triple-negative breast cancer (TNBC) is typically treated with chemotherapeutic agents, including carboplatin (Cb), an DNA platinating agent. The O6-methylguanine-DNA-methyltransferase gene (MGMT) encodes for the protein O6-alkylguanine-DNA-alkyltransferase (MGMT protein). MGMT protein is involved in DNA repair mechanisms to remove mutagenic and cytotoxic adducts from O6-guanine in DNA. In glioblastoma multiforme, MGMT methylation status is a predictive biomarker for increased response to temozolomide therapy. It has been suggested, that MGMT protein may have relevance for cellular adaptation and could have an influence on resistance to carboplatin therapy. We investigated the influence of MGMT promoter methylation on pathologic complete response and survival of patients with TNBC treated in the neoadjuvant GeparSixto trial. In 174 of 210 available TNBC tumors a valid MGMT promoter methylation status was determined by pyrosequencing of 5 CpG islands. In 21.8%, we detected a mean MGMT promoter methylation >10%. Overall, MGMT promoter methylation was not significantly associated with pathological complete response (pCR) rate. After stratification for the two therapy arms with and without Cb no statistically significant differences in therapy response rates between the two MGMT promoter methylation groups could be observed. Our results show that different MGMT promoter methylation status is not related to different chemotherapy response rates in the TNBC setting in GeparSixto.


Assuntos
Ensaios Clínicos como Assunto , Ensaios Clínicos Fase II como Assunto , Metilação de DNA , Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/genética , Regiões Promotoras Genéticas/genética , Análise de Sequência de DNA , Neoplasias de Mama Triplo Negativas/genética , Proteínas Supressoras de Tumor/genética , Biópsia , Estudos de Coortes , Ilhas de CpG/genética , Humanos , Estudos Retrospectivos , Análise de Sobrevida , Neoplasias de Mama Triplo Negativas/patologia
17.
Medicine (Baltimore) ; 99(32): e21457, 2020 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-32769873

RESUMO

INTRODUCTION: Human epidermal growth factor receptor 2 (HER2) gene amplification and mutations have emerged as oncogenic drivers and therapeutic targets not limited to breast and gastric cancers, but also in a variety of cancers. However, even if an actionable gene alteration is found, the incidence of HER2 amplification in these cancers is less than 5%. It is too difficult to conduct a conventional randomized, controlled trial in a rare fraction. Therefore, we have designed a organ-agnostic basket study, which covers a variety of solid cancers harboring HER2 amplification, in 1 study protocol. METHODS/DESIGN: This trial is a multicenter, single-arm, basket phase 2 study in Japan. Patients with solid cancers harboring HER2 amplification that have progressed with standard treatment, or rare cancers for which there is no standard treatment, will be eligible. Target cancers include bile duct, urothelial, uterine, ovarian, and other solid cancers where HER2 amplification is detected by comprehensive genomic profiling using next-generation sequencing technology. A total of 38 patients will be treated with combination therapy with trastuzumab and pertuzumab every 3 weeks until disease progression, unmanageable toxicity, death, or patient refusal. The primary endpoint is the objective response rate, and secondary endpoints are progression-free survival, overall survival, and duration of response. DISCUSSION: The aim of this trial is to evaluate the safety and efficacy of combination therapy with trastuzumab and pertuzumab in patients with locally advanced or metastatic, solid cancers harboring HER2 amplification. Instead of focusing on 1 organ type, our trial design uses a basket study focusing on HER2 amplification, regardless of the site or origin of the cancer. The results of our study will advance clinical and scientific knowledge concerning the treatment of locally advanced, rare solid cancers harboring HER2 amplification, using the combination of trastuzumab and pertuzumab. TRIAL REGISTRATION: This trial was registered in Japan Registry of Clinical Trials (jCRT) on February 25, 2019, as jRCT2031180150.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Neoplasias/tratamento farmacológico , Neoplasias/genética , Receptor ErbB-2/genética , Trastuzumab/uso terapêutico , Ensaios Clínicos Fase II como Assunto , Quimioterapia Combinada , Humanos , Japão , Estudos Multicêntricos como Assunto , Neoplasias/patologia
19.
Cancer Treat Rev ; 88: 102058, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32619864

RESUMO

Soft tissue sarcomas constitute 1% of adult malignant tumors. They are a heterogeneous group of more than 50 different histologic types. Isolated limb perfusion is an established treatment strategy for locally advanced sarcomas. Since its adoption for sarcomas in 1992, after the addition of TNFα, few modifications have been done and although indications for the procedure are essentially the same across centers, technical details vary widely. The procedures mainly involves a 60 min perfusion with melphalan and TNFα under mild hyperthermia, achieving a limb preservation rate of 72-96%; with an overall response rates from 72 to 82.5% and an acceptable toxicity according to the Wieberdink scale. The local failure rate is 27% after a median follow up of 14-31 months compared to 40% of distant recurrences after a follow up of 12-22 months. Currently there is no consensus regarding the benefit of ILP per histotype, and the value of addition of radiotherapy or systemic treatment. Further developments towards individualized treatments will provide a better understanding of the population that can derive maximum benefit of ILP with the least morbidity.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Quimioterapia do Câncer por Perfusão Regional/métodos , Sarcoma/tratamento farmacológico , Neoplasias de Tecidos Moles/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Quimioterapia do Câncer por Perfusão Regional/efeitos adversos , Quimioterapia do Câncer por Perfusão Regional/tendências , Ensaios Clínicos Fase II como Assunto , Extremidades/irrigação sanguínea , Extremidades/patologia , Humanos , Hipertermia Induzida/métodos , Melfalan/administração & dosagem , Melfalan/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Sarcoma/patologia , Neoplasias de Tecidos Moles/patologia , Fator de Necrose Tumoral alfa/administração & dosagem , Fator de Necrose Tumoral alfa/efeitos adversos
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