RESUMEN
BACKGROUND: OCTOVA compared the efficacy of olaparib (O) versus weekly paclitaxel (wP) or olaparib + cediranib (O + C) in recurrent ovarian cancer (OC). AIMS: The main aim of the OCTOVA trial was to determine the progression-free survival (PFS) of olaparib (O) versus the oral combination of olaparib plus cediranib (O + C) and weekly paclitaxel (wP) in recurrent ovarian cancer (OC). METHODS: In total, 139 participants who had relapsed within 12 months of platinum therapy were randomised to O (300 mg twice daily), wP (80 mg/m2 d1,8,15, q28) or O + C (300 mg twice daily/20 mg daily, respectively). The primary endpoint was progression-free survival (PFS) of olaparib (O) versus olaparib plus cediranib (O + C) or weekly paclitaxel (wP). The sample size was calculated to observe a PFS hazard ratio (HR) 0.64 in favour of O + C compared to O (20% one-sided type I error, 80% power). RESULTS: The majority had platinum-resistant disease (90%), 22% prior PARPi, 34% prior anti-angiogenic therapy, 30% germline BRCA1/2 mutations. The PFS was increased for O + C vs O (O + C 5.4 mo (2.3, 9.6): O 3.7 mo (1.8, 7.6) HR = 0.73; 60% CI: 0.59, 0.89; P = 0.1) and no different between wP and O (wP 3.9 m (1.9, 9.1); O 3.7 mo (1.8, 7.6) HR = 0.89, 60% CI: 0.72, 1.09; P = 0.69). The main treatment-related adverse events included manageable diarrhoea (4% Grade 3) and hypertension (4% Grade 3) in the O + C arm. DISCUSSION: OCTOVA demonstrated the activity of O + C in women with recurrent disease, offering a potential non-chemotherapy option. TRIAL REGISTRATION: ISRCTN14784018, registered on 19th January 2018 http://www.isrctn.com/ISRCTN14784018 .
Asunto(s)
Indoles , Neoplasias Ováricas , Piperazinas , Quinazolinas , Humanos , Femenino , Neoplasias Ováricas/genética , Proteína BRCA1/genética , Proteína BRCA2/genética , Recurrencia Local de Neoplasia/genética , Carcinoma Epitelial de Ovario/tratamiento farmacológico , Ftalazinas/efectos adversos , Paclitaxel/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversosRESUMEN
INTRODUCTION: Severe Graves' disease is a life-changing condition with poor outcomes from currently available treatments. It is caused by directly pathogenic thyroid-stimulating hormone receptor-stimulating antibodies (TRAb), which are secreted from plasma cells. The human anti-CD38 monoclonal antibody daratumumab was developed to target plasma cells which express high levels of CD38, and is currently licensed for treatment of the plasma cell malignancy, myeloma. However, it can also deplete benign plasma cells with the potential to reduce TRAb and alter the natural history of severe Graves' disease. This study aims to establish proof of concept that daratumumab has efficacy in patients with severe Graves' disease and will provide important data to inform a choice of dosing regimen for subsequent trials. METHODS AND ANALYSIS: The Graves-PCD trial aims to determine if daratumumab modulates the humoral immune response in patients with severe Graves' disease, and if so, over what time period, and to find an optimal dose. It is a single-blinded, randomised, dose-finding, adaptive trial using four different doses of daratumumab or placebo in 30 adult patients. Part 1 of the trial is dose-finding and, following an interim analysis, in part 2, the remaining patients will be randomised between the chosen dose(s) from the interim analysis or placebo. The primary outcome is the percentage change in serum TRAb from baseline to 12 weeks. ETHICS AND DISSEMINATION: The trial received a favourable ethical opinion from London-Hampstead Research Ethics Committee (reference 21/LO/0449). The results of this trial will be disseminated at international meetings, in the peer-reviewed literature and through partner patient group newsletters and presentations at patient education events. TRIAL REGISTRATION NUMBER: ISRCTN81162400.
Asunto(s)
Anticuerpos Monoclonales , Enfermedad de Graves , Humanos , Enfermedad de Graves/tratamiento farmacológico , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales/administración & dosificación , Ensayos Clínicos Controlados Aleatorios como Asunto , Células Plasmáticas/efectos de los fármacos , Método Simple Ciego , Adulto , Masculino , Femenino , Relación Dosis-Respuesta a DrogaRESUMEN
INTRODUCTION: Characterised by chronic inflammation of the gastrointestinal tract, inflammatory bowel disease (IBD) symptoms including diarrhoea, abdominal pain and fatigue can significantly impact patient's quality of life. Therapeutic developments in the last 20 years have revolutionised treatment. However, clinical trials and real-world data show primary non-response rates up to 40%. A significant challenge is an inability to predict which treatment will benefit individual patients.Current understanding of IBD pathogenesis implicates complex interactions between host genetics and the gut microbiome. Most cohorts studying the gut microbiota to date have been underpowered, examined single treatments and produced heterogeneous results. Lack of cross-treatment comparisons and well-powered independent replication cohorts hampers the ability to infer real-world utility of predictive signatures.IBD-RESPONSE will use multi-omic data to create a predictive tool for treatment response. Future patient benefit may include development of biomarker-based treatment stratification or manipulation of intestinal microbial targets. IBD-RESPONSE and downstream studies have the potential to improve quality of life, reduce patient risk and reduce expenditure on ineffective treatments. METHODS AND ANALYSIS: This prospective, multicentre, observational study will identify and validate a predictive model for response to advanced IBD therapies, incorporating gut microbiome, metabolome, single-cell transcriptome, human genome, dietary and clinical data. 1325 participants commencing advanced therapies will be recruited from ~40 UK sites. Data will be collected at baseline, week 14 and week 54. The primary outcome is week 14 clinical response. Secondary outcomes include clinical remission, loss of response in week 14 responders, corticosteroid-free response/remission, time to treatment escalation and change in patient-reported outcome measures. ETHICS AND DISSEMINATION: Ethical approval was obtained from the Wales Research Ethics Committee 5 (ref: 21/WA/0228). Recruitment is ongoing. Following study completion, results will be submitted for publication in peer-reviewed journals and presented at scientific meetings. Publications will be summarised at www.ibd-response.co.uk. TRIAL REGISTRATION NUMBER: ISRCTN96296121.