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1.
Bull Cancer ; 107(5S): eS16-eS21, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32620211

RESUMO

Background Metastatic Squamous cell Penile Carcinoma (mSCPC) is an orphan disease with a virally induced oncogenesis. PD-L1 expression rate is around 60% with a strong correlation between PD-L1 in the primary tumour and metastases. The first line systemic treatment relies on platinum-based chemotherapies with a median progression free survival and overall survival around 7.5 and 16 months, respectively. Immunotherapies targeting PD-1/PD-L1 axis are effective in other squamous cell or HPV related cancers. Methods PULSE is a prospective multicenter open label single arm phase II study. Thirty-two patients will be enrolled after a radiological assessment showing a non-progressive disease after 3 to 6 cycles of a first line platinum-based polychemotherapy. Patients will receive Avelumab injections 10mg/ kg every two weeks until progression or unacceptable toxicity. The primary endpoint will be the progression free survival (PFS) according to RECIST v1.1 criteria. Secondary endpoints will include PFS according to iRECIST criteria, overall survival, quality of life, safety. Ancillary explorations will include assessing blood and tissue biomarkers for association with clinical benefit. Discussion After the first line, the prognosis remains poor with no consensus on a second line systemic treatment in locally advanced or mSCPC. PULSE trial is the first study that assess an anti PD-L1 immunotherapy in maintenance among patients with locally advanced or mSCPC. NCT NUMBER : NCT03774901.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Carcinoma de Células Escamosas/tratamento farmacológico , Ensaios Clínicos Fase II como Assunto/métodos , Quimioterapia de Manutenção , Estudos Multicêntricos como Assunto/métodos , Neoplasias Penianas/tratamento farmacológico , Compostos de Platina/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Antineoplásicos Imunológicos/efeitos adversos , Carcinoma de Células Escamosas/secundário , Quimioterapia Combinada , Humanos , Imunoterapia , Masculino , Neoplasias Penianas/patologia , Intervalo Livre de Progressão , Estudos Prospectivos
2.
Bull Cancer ; 107(5S): eS22-eS27, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32620212

RESUMO

BACKGROUND: The nivolumab-ipilimumab combination provides an overall response rate of 42% in first-line metastatic treatment of clear cell renal carcinoma (mccRCC). To date, there is no robust predictive biomarker of response to immune checkpoint inhibitor (ICI). In addition, severe autoimmune disorders occur more frequently with ICI combination than with ICI alone. The objective of this study is to compare the efficacy of ICI alone or in combination in patients according to tumor molecular characteristics. METHODS: Using a 35-gene expression mRNA signature, patients were divided into 4 molecular groups (1 to 4). Patients in groups 1 and 4 were randomized to receive nivolumab alone (arms 1A and 4A) or nivolumab plus ipilimumab for 4 injections followed by nivolumab alone (arms 1B and 4B). Patients in groups 2 and 3 were randomized to receive nivolumab plus ipilimumab followed by nivolumab alone (arms 2B and 3B) or a tyrosine kinase inhibitor (sunitinib or pazopanib at the investigator's choice (arms 2C and 3C)). The main objective is the overall response rate by treatment and molecular group. DISCUSSION: BIONIKK is the first trial in mccRCC to study the personalization of treatment with ICI or TKI according to tumor molecular characteristics in mccRCC. This trial is the most appropriate to prospectively identify biomarkers of response to nivolumab used alone or in combination or TKI monotherapy in patients with mccRCC. NCT02960906.


Assuntos
Antineoplásicos Imunológicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Ensaios Clínicos Fase II como Assunto/métodos , Ipilimumab/administração & dosagem , Neoplasias Renais/tratamento farmacológico , Nivolumabe/administração & dosagem , Inibidores de Proteínas Quinases/administração & dosagem , Pirimidinas/administração & dosagem , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos , Sulfonamidas/administração & dosagem , Sunitinibe/administração & dosagem , Biomarcadores Tumorais , Quimioterapia Combinada , Humanos , Neoplasias Renais/patologia , Metástase Neoplásica , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores
3.
Bull Cancer ; 107(5S): eS8-eS15, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32620213

RESUMO

BACKGROUND: Neoadjuvant cisplatin-based chemotherapy (NAC) is the standard of care in localized muscle-invasive bladder cancer (MIBC). However, 60-70% of patients have residual tumor after NAC. Based on the overall response rate observed in the metastatic setting, ddMVAC is the most commonly used NAC regimen in Europe. The emergence of immune checkpoint inhibitor (ICI) in the metastatic setting raises the question if the combination of chemo plus ICI could increase the pCR rate. METHODS/DESIGN: NEMIO is a French open-label randomized phase I/II trial assessing in the neoadjuvant setting the combination of ddMVAC plus durvalumab alone or with tremelimumab: 4 cycles of ddMVAC/2 weeks + 2 cycles of Durvalumab +/- Tremelimumab/4 weeks. Cystectomy is performed 4-8 weeks after the last dose of ddMVAC. Six pts will be included in each arm in a safety run-in cohort to evaluate the toxicity rate. Each arm will be expanded to a maximum of 60 pts. The primary endpoint of the safety run-in phase will be the rate of grade 3/4 treatment-related adverse events G3/4 TRAE. The primary endpoint of the phase II will be the pathological response rate and G 3/4 TRAE. Exploratory endpoints will include biomarkers of response and resistance to the combo. A total of 120 patients will be included in 15 French centers and we expect the recruitment to be completed in 2021. DISCUSSION: NEMIO trial will assess for the first time the tolerance and the efficacy of ddMVAC regimen associated with checkpoints inhibitors as neoadjuvant treatment in localized MIBC. NCT number: NCT03549715. Registered on June 8, 2018.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Carcinoma de Células de Transição/tratamento farmacológico , Ensaios Clínicos Fase II como Assunto/métodos , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos , Neoplasias da Bexiga Urinária/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células de Transição/patologia , Cisplatino/uso terapêutico , Doxorrubicina/uso terapêutico , Humanos , Metotrexato/uso terapêutico , Terapia Neoadjuvante , Invasividade Neoplásica , Resultado do Tratamento , Neoplasias da Bexiga Urinária/patologia , Vimblastina/uso terapêutico
4.
Bull Cancer ; 107(5S): eS1-eS7, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32620210

RESUMO

BACKGROUND: The standard treatment in first line of advanced or metastatic urothelial bladder cancer (MBC) is the association of Gemcitabine and Cisplatin (GC). Avelumab, an anti-PD-L1 agent, has recently demonstrated efficacy. The objective is to evaluate the combination of these 3 agents. METHODS: This phase II randomized open-label study, evaluated if GC-avelumab increases response rate and duration of response of patients in 1st line treatment for MBC compared to GC. Severe toxicities should not overlap and be acceptable. The two co-primary end points are the objective response rate and the incidence of severe toxicity after six cycles of treatment. The study will recruit 90 participants, randomized in two arms (1:2), GC (gemcitabine 1 000 mg/m2/j, J1,J8, Cisplatine 70 mg/m2, J1 = J21), and GC-avelumab (10 mg/Kg/3 semaines). Randomization will be stratified on Karnofsky status (≥ 80 % vs. < 80 %) and visceral vs non visceral metastases. The duration of the inclusion period is 24 months, with a duration of participation of each patient of 18 months and a total study duration of 42 months. DISCUSSION: If both efficacy and safety of the association of GC+avelumab are in the range of acceptable through this specific study design, this will support a subsequent randomized phase III study comparing both arms with an overall survival end-point. In addition, the evaluation of predictive parameters to be confirmed (e.g. the impact of tumor PD-L1 expression) or other immunological parameters, may support a selection of the population. NCT number : NCT03324282.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Carcinoma de Células de Transição/tratamento farmacológico , Cisplatino/administração & dosagem , Ensaios Clínicos Fase II como Assunto/métodos , Desoxicitidina/análogos & derivados , Estudos Multicêntricos como Assunto/métodos , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos , Neoplasias da Bexiga Urinária/tratamento farmacológico , Carcinoma de Células de Transição/patologia , Desoxicitidina/administração & dosagem , Humanos , Invasividade Neoplásica , Estudos Prospectivos , Neoplasias da Bexiga Urinária/patologia
5.
Ann Hematol ; 99(8): 1701-1707, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32583086

RESUMO

COVID-19 pandemia is a major health emergency causing hundreds of deaths worldwide. The high reported morbidity has been related to hypoxia and inflammation leading to endothelial dysfunction and aberrant coagulation in small and large vessels. This review addresses some of the pathways leading to endothelial derangement, such as complement, HIF-1α, and ABL tyrosine kinases. This review also highlights potential targets for prevention and therapy of COVID-19-related organ damage and discusses the role of marketed drugs, such as eculizumab and imatinib, as suitable candidates for clinical trials.


Assuntos
Betacoronavirus , Inativadores do Complemento/administração & dosagem , Infecções por Coronavirus/metabolismo , Sistemas de Liberação de Medicamentos/métodos , Endotélio Vascular/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Pneumonia Viral/metabolismo , Proteínas Tirosina Quinases/metabolismo , Anticorpos Monoclonais Humanizados/administração & dosagem , Ensaios Clínicos Fase II como Assunto/métodos , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/patologia , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/patologia , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/antagonistas & inibidores , Mesilato de Imatinib/administração & dosagem , Pandemias/prevenção & controle , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/patologia , Proteínas Tirosina Quinases/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia
6.
J Med Chem ; 63(10): 5100-5101, 2020 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-32401033

RESUMO

Bruton's tyrosine kinase (BTK) is a major drug target for B-cell related malignancies; however, existing BTK inhibitors approved for cancer treatment have significant off-targets that limit their use for autoimmune and inflammatory diseases. Remibrutinib (LOU064) is a novel covalent BTK inhibitor that binds an inactive BTK conformation, which affords it unprecedented selectivity. Its optimization led to rapid BTK engagement in vivo and fast clearance, further limiting systemic exposure. Remibrutinib is currently in phase 2 clinical trials for treatment of chronic urticaria and Sjoegren's syndrome.


Assuntos
Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Tirosina Quinase da Agamaglobulinemia/metabolismo , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/metabolismo , Tirosina Quinase da Agamaglobulinemia/química , Linfócitos B/efeitos dos fármacos , Linfócitos B/metabolismo , Ensaios Clínicos Fase II como Assunto/métodos , Humanos , Inibidores de Proteínas Quinases/química , Síndrome de Sjogren/tratamento farmacológico , Síndrome de Sjogren/metabolismo , Urticária/tratamento farmacológico , Urticária/metabolismo
8.
Epilepsy Behav ; 103(Pt A): 106864, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31937513

RESUMO

OBJECTIVE: The objective of this analysis was to provide a comprehensive analysis of safety data for adjunctive brivaracetam (BRV), an antiepileptic drug (AED) of the racetam class, for treatment of focal seizures in patients with epilepsy. METHODS: Data were pooled from two phase II, placebo-controlled, double-blind, dose-ranging trials (N01114 [ClinicalTrials.gov: NCT00175929], N01193 [NCT00175825]) and three phase III, placebo-controlled, double-blind, 12-week trials (N01252 [NCT00490035], N01253 [NCT00464269], and N01358 [NCT01261325]) in patients aged ≥16 years with focal seizures, as well as a phase III, placebo-controlled, double-blind, 16-week trial in patients aged ≥16 years with focal or generalized epilepsy (N01254 [NCT00504881]). Data are presented for the approved therapeutic dose range of 50-200 mg/day. Data for BRV administered intravenously (25-150 mg doses) were pooled separately from one phase III trial (N01258 NCT01405508]) and two clinical pharmacology trials (N01256 [Part B] [UCB Pharma, data on file]; EP0007 [NCT01796899]). Adverse events (AEs) of interest were summarized in relevant categories. RESULTS: The safety pool comprised 1957 patients: 1271 receiving adjunctive BRV and 686 receiving placebo. Overall, the incidence of treatment-emergent adverse events (TEAEs) was 66.9% with BRV versus 62.8% with placebo. The most frequently reported TEAEs with BRV (≥5% of patients) versus placebo were somnolence (13.3% vs. 7.9%), headache (10.5% vs. 11.5%), dizziness (10.0% vs. 7.0%), and fatigue (8.2% vs. 4.2%). Incidence of psychiatric disorder-related TEAEs was 11.3% with BRV versus 8.2% with placebo. Behavioral disorder-related TEAE incidence was low (4.0% with BRV vs. 2.5% with placebo). Irritability was reported in 2.7% of BRV-treated patients vs. 1.5% of patients receiving placebo; anger, aggression, and agitation were each reported by ≤1% of patients receiving BRV. Treatment-emergent adverse events potentially associated with psychosis were psychotic disorder (three patients on BRV vs. two patients on placebo), auditory hallucination, illusion, visual hallucination (one patient each on BRV), epileptic psychosis, and hallucination (one patient each on placebo). No additional safety concerns were identified in patients with intravenous (IV) BRV administration (n = 104). CONCLUSIONS: These safety data for adjunctive BRV support its acceptable safety and tolerability profile.


Assuntos
Anticonvulsivantes/administração & dosagem , Anticonvulsivantes/efeitos adversos , Epilepsia/tratamento farmacológico , Pirrolidinonas/administração & dosagem , Pirrolidinonas/efeitos adversos , Administração Intravenosa , Ensaios Clínicos Fase II como Assunto/métodos , Ensaios Clínicos Fase III como Assunto/métodos , Tontura/induzido quimicamente , Método Duplo-Cego , Quimioterapia Combinada , Epilepsia/diagnóstico , Fadiga/induzido quimicamente , Humanos , Resultado do Tratamento
9.
Eur J Cancer ; 126: 65-73, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31923729

RESUMO

INTRODUCTION: T-DM1 has been approved for the treatment of HER2+ breast cancer. Cardiac dysfunction is a side effect of trastuzumab, a component of T-DM1. However, little is known about T-DM1-associated cardiotoxicity. METHODS: We have conducted a pooled analysis of T-DM1 trials in advanced HER2+ breast cancer cases to understand the incidence, clinical presentation as well as to establish possible risk factors for T-DM1-associated cardiotoxicity. The primary endpoint was the incidence of cardiac events (CEs). CEs were categorized as follows: (1) congestive heart failure (CHF) or grade 3/4 LVEF drop; (2) cardiac ischemia, (3) cardiac arrhythmia, (4) grade 1/2 LVEF drop. Secondary endpoints included CE recovery rate and impact of CEs on treatment discontinuation. Logistic regression was used to assess possible risk factors for CEs. RESULTS: Individual patient-level data from 1961 patients exposed to T-DM1 in seven trials were pooled. Of these, 1544 received T-DM1 and 417 T-DM1 + pertuzumab. CHF/LVEF drop grade 3/4 was reported in 0.71%, cardiac ischemia in 0.1%, cardiac arrhythmia in 0.71% and grade 1/2 LVEF drop in 2.04%. The total CE rate was 3.37% (95% confidence interval (CI), 2.6%-4.3%). Multivariate analysis showed patient's age ≥65 (OR 3.0; 95% CI, 1.77-5.14; P-value <0.001) and baseline LVEF<55% (OR 2.62; 95% CI, 1.29-5.32; P-value 0.008) as risk factors. CEs resolved in most (79%) patients after treatment discontinuation. CONCLUSION: The incidence of CEs in patients receiving T-DM1 was low. Older patients receiving T-DM1 should be carefully followed for cardiac safety during treatment.


Assuntos
Ado-Trastuzumab Emtansina/efeitos adversos , Arritmias Cardíacas/diagnóstico , Neoplasias da Mama/tratamento farmacológico , Insuficiência Cardíaca/diagnóstico , Isquemia Miocárdica/diagnóstico , Ado-Trastuzumab Emtansina/uso terapêutico , Idoso , Antineoplásicos Imunológicos/efeitos adversos , Antineoplásicos Imunológicos/uso terapêutico , Arritmias Cardíacas/induzido quimicamente , Neoplasias da Mama/metabolismo , Cardiotoxicidade/diagnóstico , Cardiotoxicidade/etiologia , Cardiotoxicidade/fisiopatologia , Ensaios Clínicos Fase II como Assunto/métodos , Ensaios Clínicos Fase II como Assunto/estatística & dados numéricos , Ensaios Clínicos Fase III como Assunto/métodos , Ensaios Clínicos Fase III como Assunto/estatística & dados numéricos , Feminino , Insuficiência Cardíaca/induzido quimicamente , Humanos , Pessoa de Meia-Idade , Estudos Multicêntricos como Assunto/métodos , Estudos Multicêntricos como Assunto/estatística & dados numéricos , Isquemia Miocárdica/induzido quimicamente , Receptor ErbB-2/metabolismo
10.
J Clin Epidemiol ; 119: 100-108, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31816417

RESUMO

OBJECTIVE: Persistent efforts have been made to promote clinical trial transparency, which included encouraging trial registration and prospective registration, as well as protocol disclosure. This study aims to analyze the extent of registration, prospective registration and protocol disclosure in oncology clinical trials and their changing trends. STUDY DESIGN AND SETTING: All phase II and phase III oncology clinical trials published in 5 major journals, the Annals of Oncology, the Journal of Clinical Oncology, JAMA Oncology, The Lancet Oncology, and The New England Journal of Medicine, between January 2013 and December 2017, were included. Data on trial characteristics as well as registration status and availability of protocol and its location were collected. RESULTS: In total, 625 articles were included, 92% were registered, of which 76% were prospectively registered. Overall, 27% provided protocols. Increasing trends were observed in registration, prospective registration, and protocol disclosure (all P < 0.001). Studies with enrollment number larger than median number were more likely to be registered (adjusted odds ratio (aOR), 3.14 [95% confidence interval (CI), 1.21-8.15]) and to provide protocols (aOR, 3.84 [95% CI, 2.24-6.57]) than those with smaller enrollment number. Studies with nonindustry funding was less likely to be prospectively registered (aOR, 0.37 [95% CI, 0.25-0.55]) but more likely to provide protocols (aOR, 1.69 [95% CI, 1.13-2.52]) than those with industry funding only. CONCLUSION: Although the rates of registration, prospective registration, and protocol disclosure of oncology trials have significantly increased over the years, there is still room for improvement.


Assuntos
Ensaios Clínicos Fase II como Assunto/métodos , Ensaios Clínicos Fase III como Assunto/métodos , Revelação , Oncologia/métodos , Protocolos Clínicos , Humanos
11.
J Natl Cancer Inst ; 112(4): 335-342, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-31651981

RESUMO

BACKGROUND: The US Food and Drug Administration's accelerated approval and later withdrawal of bevacizumab in patients with metastatic breast cancer (mBC) is a seminal case for ongoing debates about the validity of using progression-free survival (PFS) as a surrogate measure for overall survival (OS) in cancer drug approvals. We systematically reviewed and meta-analyzed the evidence around bevacizumab's regulatory approval and withdrawal in mBC. METHODS: We searched for all published phase II or III clinical trials testing bevacizumab as a first-line therapy for patients with mBC. Data were extracted on trial demographics, interventions, and outcomes. Descriptive analysis was stratified by whether the trial was initiated before, during, or after the accelerated approval. We used a cumulative random-effects meta-analysis to assess the evolution of evidence of the effect of bevacizumab on PFS and OS. We estimated the association between the trial-level PFS and OS effect using a nonlinear mixed-regression model. RESULTS: Fifty-two studies were included. Trial activity dramatically dropped after the accelerated approval was withdrawn. Eight clinical trials reported hazard ratios (hazard ratios) and were meta-analyzed. The cumulative hazard ratio for PFS was 0.72 (95% CI = 0.65 to 0.79), and the cumulative hazard ratio for OS was 0.90 (95% CI = 0.80 to 1.01). The regression model showed a statistically nonsignificant association between PFS benefit and OS benefit (ß = 0.43, SE = 0.81). CONCLUSION: The US Food and Drug Administration's decision-making in this case was consistent with the evolving state of evidence. However, the fact that seven clinical trials are insufficient to conclude validity (or lack thereof) for a trial-level surrogate suggests that it would be more efficient to conduct trials using the more clinically meaningful endpoints.


Assuntos
Bevacizumab/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Aprovação de Drogas/métodos , Antineoplásicos Imunológicos/uso terapêutico , Neoplasias da Mama/patologia , Ensaios Clínicos Fase II como Assunto/métodos , Ensaios Clínicos Fase II como Assunto/estatística & dados numéricos , Ensaios Clínicos Fase III como Assunto/métodos , Ensaios Clínicos Fase III como Assunto/estatística & dados numéricos , Tomada de Decisões , Determinação de Ponto Final , Feminino , Humanos , Legislação de Medicamentos , Metástase Neoplásica , Dinâmica não Linear , Intervalo Livre de Progressão , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos , Ensaios Clínicos Controlados Aleatórios como Assunto/estatística & dados numéricos , Análise de Regressão , Taxa de Sobrevida , Estados Unidos , United States Food and Drug Administration
12.
Drug Saf ; 43(2): 119-134, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31679129

RESUMO

INTRODUCTION: Individualised benefit-harm assessments can help identify patient-perceived benefits and harms of a treatment, and associated trade-offs that may influence patients' willingness to use a treatment. This research presents the first use of a patient-reported outcome measure designed to assess patient-perceived benefits and disadvantages of drugs received during clinical studies. METHODS: The Patient's Qualitative Assessment of Treatment (PQAT) was developed in English and cognitively tested with US (n = 4) and Canadian (n = 3) patients with type 1 and type 2 diabetes mellitus (T2DM). The revised version of the PQAT comprises three qualitative open-ended questions focused on the benefits and disadvantages of treatment and reasons why patients would choose to continue/discontinue treatment. A final quantitative question asks patients to evaluate the balance between benefits and disadvantages using a 7-point scale. The revised version of the questionnaire was administered as an exploratory endpoint in a phase II clinical trial for a new injectable treatment for T2DM. Qualitative data were analysed using thematic analysis, and relationships between qualitative and quantitative data were identified. RESULTS: Patient-reported benefits of treatment administered during the clinical trial included clinical markers of efficacy and subjective markers. Disadvantages reported by patients were mainly related to drug adverse effects or to the mode of administration. Of the 57 patients completing the PQAT, 70.2% reported being willing to continue treatment, with 59.6% reporting that the benefits outweighed the disadvantages. The reported benefits of feeling better and improved energy levels were more likely to be associated with a more positive ratio (70% and 71.4%, respectively), while the disadvantages of fatigue, headaches, and stomach pain were associated with a negative ratio and patients not being willing to continue the treatment. CONCLUSIONS: The PQAT is a unique patient-reported outcome tool designed to aid understanding patients' real experience of benefits and disadvantages of a treatment. It combines the richness of qualitative data with quantitative data-information valuable for various stakeholders to make well-informed treatment decisions. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02973321.


Assuntos
Ensaios Clínicos Fase II como Assunto/métodos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Medidas de Resultados Relatados pelo Paciente , Adulto , Idoso , Determinação de Ponto Final/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Inquéritos e Questionários
13.
J Natl Cancer Inst ; 112(1): 38-45, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30924863

RESUMO

BACKGROUND: Immunotherapies have revolutionized cancer treatment. Unlike chemotherapies, immune agents often take longer to show benefit, and the complex and unique mechanism of action of these agents renders the use of multiple endpoints more appropriate in some trials. These new features of immunotherapy make conventional phase II trial designs, which assume a single binary endpoint that is quickly ascertainable, inefficient and dysfunctional. METHODS: We propose a flexible and efficient time-to-event Bayesian optimal phase II (TOP) design. The TOP design is efficient in that it allows real-time "go/no-go" interim decision making in the presence of late-onset responses by using all available data and maximizes statistical power for detecting effective treatments. TOP is flexible in the number of interim looks and capable of handling simple and complicated endpoints under a unified framework. We conduct simulation studies to evaluate the operating characteristics of the TOP design. RESULTS: In the considered trial settings, compared to some existing Bayesian designs, the TOP design shortens the trial duration by 4-10 months and improves the power to detect effective treatment up to 90%, with well-controlled type I errors. CONCLUSIONS: The TOP design is transparent and easy to implement, as its decision rules can be tabulated and included in the protocol prior to the conduct of the trial. The TOP design provides a flexible, efficient, and easy-to-implement method to accelerate and improve the development of immunotherapies.


Assuntos
Teorema de Bayes , Ensaios Clínicos Fase II como Assunto/métodos , Ensaios Clínicos Fase II como Assunto/normas , Imunoterapia , Oncologia , Projetos de Pesquisa , Software , Algoritmos , Simulação por Computador , Determinação de Ponto Final , Humanos , Imunoterapia/métodos , Imunoterapia/normas , Oncologia/métodos , Oncologia/normas , Prognóstico , Tamanho da Amostra , Resultado do Tratamento
14.
J Orthop Surg Res ; 14(1): 441, 2019 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-31842921

RESUMO

INTRODUCTION: Patellar tendon overuse injuries are common in athletes. Imaging may show a change in tissue structure with tendon thickening and disruption of the intratendinous substance. We wish to test the hypothesis that both autologous bone marrow expanded mesenchymal stem cells and autologous leukocyte-poor platelet-rich plasma (LP-PRP) implanted into the area of the disrupted tendinopathic patellar tendon will restore function, but tendon regeneration tissue will only be observed in the subjects treated with autologous bone marrow expanded mesenchymal stem cells. METHODS AND ANALYSIS: This is a single-centre, pilot phase I/II, double-blinded clinical trial with randomisation with active control. Twenty patients with a diagnosis of patellar tendinopathy with imaging changes (tendon thickening and disruption of the intratendinous substance at the proximal portion of the patellar tendon) will be randomised in a 1:1 ratio to receive a local injection of either bone-marrow autologous mesenchymal stem cells (MSC), isolated and cultured under GMP at The Institute of Biology and Molecular Genetics (IBGM) (Spain) or P-PRP. The study will have two aims: first, to ascertain whether a clinically relevant improvement after 3, 6 and 12 months according to the visual analogue scale (VAS), Victorian Institute of Sport Assessment for patellar tendons (VISA-P) and dynamometry scales (DYN) will be achieved; and second, to ascertain whether the proposed intervention will restore tendon structure as determined by ultrasonography (US), Doppler ultrasonography (DUS), and innovative MRI and ultrasound techniques: Magnetic Resonance T2 FAT SAT (UTE, Ultrashort Echo TE) sequence and Ultrasound Tissue Characterization (UTC). Patients who are randomised to the P-PRP treatment group but do not achieve a satisfactory primary endpoint after 6 months will be offered treatment with MSC. TRIAL REGISTRATION: NCT03454737.


Assuntos
Transplante de Células-Tronco Mesenquimais/métodos , Células-Tronco Mesenquimais/citologia , Ligamento Patelar , Tendinopatia/terapia , Adolescente , Adulto , Ensaios Clínicos Fase I como Assunto/métodos , Ensaios Clínicos Fase II como Assunto/métodos , Método Duplo-Cego , Humanos , Imagem por Ressonância Magnética , Masculino , Transplante de Células-Tronco Mesenquimais/efeitos adversos , Pessoa de Meia-Idade , Medição da Dor/métodos , Ligamento Patelar/diagnóstico por imagem , Seleção de Pacientes , Projetos Piloto , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos , Projetos de Pesquisa , Tendinopatia/diagnóstico por imagem , Resultado do Tratamento , Ultrassonografia , Adulto Jovem
15.
Eur J Cancer ; 121: 202-209, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31593830

RESUMO

BACKGROUND: A randomised trial SHIVA01 compared the efficacy of matched molecularly targeted therapy outside their indications based on a prespecified treatment algorithm versus conventional chemotherapy in patients with metastatic solid tumours who had failed standard of care. No statistical difference was reported between the two groups in terms of progression-free survival (PFS), challenging treatment algorithm. The European Society for Medical Oncology (ESMO) Scale for Clinical Actionability of molecular Targets (ESCAT) recently defined criteria to prioritise molecular alterations (MAs) to select anticancer drugs. We aimed to retrospectively evaluate the efficacy of matched molecularly targeted agents (MTAs) given in SHIVA01 according to ESCAT tiers. PATIENTS AND METHODS: MAs used in SHIVA01 were retrospectively classified into ESCAT tiers, and PFS and overall survival (OS) were compared using log-rank tests. RESULTS: One hundred fifty-three patients were treated with matched MTAs in SHIVA01. MAs used to allocate MTAs were classified into tiers II, IIIA, IIIB and IVA according to the ESCAT. Median PFS was 2.0 months in tier II, 3.1 in tier IIIA, 1.7 in tier IIIB and 3.2 in tier IVA (p = 0.13). Median OS in tier IIIB was worse than that in tiers II, IIIA and IVA (6.3 months versus 11.7, 11.2 and 12.1, p = 0.002). CONCLUSIONS: Most MAs used to allocate therapy in SHIVA01 were shown to improve outcomes in other tumour types (tier IIIA). Worst outcome was observed in patients treated based on another type of alteration than the one reported to improve outcomes (tier IIIB), highlighting the crucial impact of the type of the alterations beyond the gene and the signalling pathway.


Assuntos
Algoritmos , Antineoplásicos/classificação , Antineoplásicos/uso terapêutico , Aprovação de Drogas , Terapia de Alvo Molecular/métodos , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Ensaios Clínicos Fase II como Assunto/métodos , Intervalo Livre de Doença , Aprovação de Drogas/métodos , Aprovação de Drogas/organização & administração , Prática Clínica Baseada em Evidências/normas , Feminino , França , Humanos , Masculino , Oncologia/organização & administração , Oncologia/normas , Pessoa de Meia-Idade , Medicina de Precisão/métodos , Prognóstico , Estudo de Prova de Conceito , Projetos de Pesquisa , Estudos Retrospectivos , Sociedades Médicas/organização & administração , Sociedades Médicas/normas , Resultado do Tratamento , Adulto Jovem
16.
Eur J Cancer ; 121: 130-143, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31574418

RESUMO

PURPOSE: Concomitant external-beam radiochemotherapy (5-fluorouracil-mitomycin C) has become the standard of care in anal cancer since the '90s. A pooled analysis of individual patient data from 7 major trials was performed quantifying the effect of radiation therapy (RT)-related parameters on the outcome of patients with anal cancer. MATERIALS AND METHODS: Pooling databases from combined modality trials, the impact of RT parameters (total dose, gap duration, OTT: overall treatment time) on outcome including locoregional failure (LRF), 5-year progression free survival (PFS) and toxicities were investigated. Individual patient data were received for 10/13 identified published studies conducted from 1987 to 2008 (n = 3031). A Cox regression model was used (landmark = 3 months after RT for first follow-up). RESULTS: After data inspection indicating severe heterogeneity between trials, only 1343 patients from 7/10 studies received were analysed (the most recent ones, since 1994; median follow-up = 4.1 years). A higher overall 5-year LRF rate [22.8% (95% confidence interval [CI] 22.3-27.3%)] significantly correlated with longer OTT (p = 0.03), larger tumour size (p < 0.001) and male gender (p = 0.045). Although significant differences were not observed, subset analyses for LRF (dose range: 50.4-59 Gy) seemed to favour lower doses (p = 0.412), and when comparing a 2-week gap versus 3 (dose: 59.4 Gy), results suggested 3 weeks might be detrimental (p = 0.245). For a 2-week gap versus none (dose range: 55-59.4 Gy), no difference was observed (p = 0.89). Five-year PFS was 65.7% (95% CI: 62.8-68.5%). Higher PFS rates were observed in women (p < 0.001), smaller tumour sizes (p < 0.001) and shorter OTT (p = 0.025). Five-year overall survival [76.7% (95% CI: 73.9%-79.3%)] correlated positively with female gender (p < 0.001), small tumour size (p = 0.027) and short OTT (p = 0.026). Descriptive toxicity data are presented. CONCLUSION: For patients receiving concurrent external-beam doublet chemoradiation, a longer OTT seems detrimental to outcome. Further trials involving modern techniques may better define optimal OTT and total dose.


Assuntos
Neoplasias do Ânus/terapia , Quimiorradioterapia/métodos , Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase III como Assunto , Fluoruracila/administração & dosagem , Mitomicina/administração & dosagem , Neoplasias do Ânus/epidemiologia , Neoplasias do Ânus/patologia , Quimiorradioterapia/efeitos adversos , Ensaios Clínicos Fase II como Assunto/métodos , Ensaios Clínicos Fase II como Assunto/estatística & dados numéricos , Ensaios Clínicos Fase III como Assunto/métodos , Ensaios Clínicos Fase III como Assunto/estatística & dados numéricos , Terapia Combinada , Fluoruracila/efeitos adversos , Humanos , Mitomicina/efeitos adversos , Recidiva Local de Neoplasia/etnologia , Recidiva Local de Neoplasia/terapia , Dosagem Radioterapêutica , Resultado do Tratamento
17.
Pharm Stat ; 18(6): 700-713, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31507079

RESUMO

We propose a two-stage design for a single arm clinical trial with an early stopping rule for futility. This design employs different endpoints to assess early stopping and efficacy. The early stopping rule is based on a criteria determined more quickly than that for efficacy. These separate criteria are also nested in the sense that efficacy is a special case of, but usually not identical to, the early stopping endpoint. The design readily allows for planning in terms of statistical significance, power, expected sample size, and expected duration. This method is illustrated with a phase II design comparing rates of disease progression in elderly patients treated for lung cancer to rates found using a historical control. In this example, the early stopping rule is based on the number of patients who exhibit progression-free survival (PFS) at 2 months post treatment follow-up. Efficacy is judged by the number of patients who have PFS at 6 months. We demonstrate our design has expected sample size and power comparable with the Simon two-stage design but exhibits shorter expected duration under a range of useful parameter values.


Assuntos
Ensaios Clínicos Fase II como Assunto/métodos , Interpretação Estatística de Dados , Término Precoce de Ensaios Clínicos/métodos , Projetos de Pesquisa , Idoso , Progressão da Doença , Determinação de Ponto Final , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Intervalo Livre de Progressão , Tamanho da Amostra , Fatores de Tempo
18.
Clin Trials ; 16(6): 635-644, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31538815

RESUMO

BACKGROUND: Phase I and Phase II clinical trials aim at identifying a dose that is safe and active. Both phases are increasingly combined. For Phase I/II trials, two main types of designs are debated: a dose-escalation stage to select the maximum tolerated dose, followed by an expansion cohort to investigate its activity (dose-escalation followed by an expansion cohort), or a joint modelling to identify the best trade-off between toxicity and activity (efficacy-toxicity). We explore this question in the context of a paediatric Phase I/II platform trial. METHODS: In series of simulations, we assessed the operating characteristics of dose-escalation followed by an expansion cohort (DE-EC) designs without and with reassessment of the maximum tolerated dose during the expansion cohort (DE-ECext) and of the efficacy-toxicity (EffTox) design. We investigated the probability to identify an active and tolerable agent, that is, the percentage of correct decision, for various dose-toxicity activity scenarios. RESULTS: For a large therapeutic index, the percentage of correct decision reached 96.0% for efficacy-toxicity versus 76.1% for dose-escalation followed by an expansion cohort versus 79.6% for DE-ECext. Conversely, when all doses were deemed not active, the percentage of correct decision was 47% versus 55.9% versus 69.2%, respectively, for efficacy-toxicity, dose-escalation followed by an expansion cohort and DE-ECext. Finally, in the case of a narrow therapeutic index, the percentage of correct decision was 48.0% versus 64.3% versus 67.2%, respectively, efficacy-toxicity, dose-escalation followed by an expansion cohort and DE-ECext. CONCLUSION: As narrow indexes are common in oncology, according to the present results, the sequential dose-escalation followed by an expansion cohort is recommended. The importance to re-estimate the maximum tolerated dose during the expansion cohort is confirmed. However, despite their theoretical advantages, Phase I/II designs are challenged by the variations in populations between the Phase I and the Phase II parts and by the lagtime in the evaluation of toxicity and activity.


Assuntos
Ensaios Clínicos Fase I como Assunto/métodos , Ensaios Clínicos Fase II como Assunto/métodos , Dose Máxima Tolerável , Projetos de Pesquisa , Estudos de Coortes , Relação Dose-Resposta a Droga , Humanos , Oncologia , Modelos Estatísticos , Pediatria
19.
Eur J Cancer ; 121: 19-28, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31526874

RESUMO

PURPOSE: We aimed to determine whether treatment effect size differed between randomised controlled phase II trials and subsequent phase III trials and examine potential predictor of positive phase III trials. METHODS: We searched MEDLINE for randomised controlled phase II studies published from January 2006 to December 2015. Matched phase III trials that investigated same intervention in the same setting of the same cancer were identified through Web of Science, ClinicalTrials.gov and conference proceedings. For each pair of phase II and phase III trials, we extracted hazard ratios (HRs) with 95% confidence intervals (CIs) for both overall survival (OS) and progression-free survival (PFS) and evaluated the differences by ratio of HRs (rHRs): the HR for phase II trial to that for phase III trial. A summary rHR was obtained through a random-effect meta-analysis. Univariable analyses were conducted to identify predictors of positive phase III trials. RESULTS: We identified 57 pairs of phase II and phase III trials. Compared with phase III trials, treatment effect sizes of PFS were, on average, 26% larger in phase II trials (rHR = 0.74, P < 0.001, 95% CI: 0.68-0.80). Treatment effect sizes of OS were 27% greater in phase II trials than in phase III trials (rHR = 0.73, P < 0.001, 95% CI: 0.66-0.79). Fifteen (26.3%) phase III trials were positive, and the only predictor of positive phase III trials was positive phase II trials CONCLUSION: Treatment effects in randomised controlled phase II trials were greater than those in matched phase III trials. Caution must be taken when interpreting promising results from randomised controlled phase II trials.


Assuntos
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 , Neoplasias/tratamento farmacológico , Ensaios Clínicos Controlados Aleatórios como Assunto/estatística & dados numéricos , Ensaios Clínicos Fase II como Assunto/métodos , Ensaios Clínicos Fase II como Assunto/normas , Ensaios Clínicos Fase III como Assunto/métodos , Interpretação Estatística de Dados , Humanos , Neoplasias/patologia , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos , Ensaios Clínicos Controlados Aleatórios como Assunto/normas , Projetos de Pesquisa , Resultado do Tratamento
20.
Clin Trials ; 16(5): 531-538, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31256630

RESUMO

BACKGROUND/AIMS: For single arm trials, a treatment is evaluated by comparing an outcome estimate to historically reported outcome estimates. Such a historically controlled trial is often analyzed as if the estimates from previous trials were known without variation and there is no trial-to-trial variation in their estimands. We develop a test of treatment efficacy and sample size calculation for historically controlled trials that considers these sources of variation. METHODS: We fit a Bayesian hierarchical model, providing a sample from the posterior predictive distribution of the outcome estimand of a new trial, which, along with the standard error of the estimate, can be used to calculate the probability that the estimate exceeds a threshold. We then calculate criteria for statistical significance as a function of the standard error of the new trial and calculate sample size as a function of difference to be detected. We apply these methods to clinical trials for amyotrophic lateral sclerosis using data from the placebo groups of 16 trials. RESULTS: We find that when attempting to detect the small to moderate effect sizes usually assumed in amyotrophic lateral sclerosis clinical trials, historically controlled trials would require a greater total number of patients than concurrently controlled trials, and only when an effect size is extraordinarily large is a historically controlled trial a reasonable alternative. We also show that utilizing patient level data for the prognostic covariates can reduce the sample size required for a historically controlled trial. CONCLUSION: This article quantifies when historically controlled trials would not provide any sample size advantage, despite dispensing with a control group.


Assuntos
Grupos Controle , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos , Tamanho da Amostra , Esclerose Amiotrófica Lateral/terapia , Teorema de Bayes , Ensaios Clínicos Fase II como Assunto/métodos , Ensaios Clínicos Fase II como Assunto/estatística & dados numéricos , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto/estatística & dados numéricos
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