Investigator choice of standard therapy versus sequential novel therapy arms in the treatment of relapsed follicular lymphoma (REFRACT): study protocol for a multi-centre, open-label, randomised, phase II platform trial

BackgroundRelapsed or refractory follicular lymphoma (rrFL) is an incurable disease associated with shorter remissions and survival after each line of standard therapy. Many promising novel, chemotherapy-free therapies are in development, but few are licensed as their role in current treatment pathways is poorly defined. MethodsThe REFRACT trial is an investigator-initiated, UK National Cancer Research Institute, open-label, multi-centre, randomised phase II platform trial aimed at accelerating clinical development of novel therapies by addressing evidence gaps. The first of the three sequential novel therapy arms is epcoritamab plus lenalidomide, to be compared with investigator choice standard therapy (ICT). Patients aged 18 years or older with biopsy proven relapsed or refractory CD20 positive, grade 1-3a follicular lymphoma and assessable disease by PET-CT are eligible. The primary outcome is complete metabolic response by PET-CT at 24 weeks using the Deauville 5-point scale and Lugano 2014 criteria. Secondary outcomes include overall metabolic response, progression-free survival, overall survival, duration of response, and quality of life assessed by EQ-5D-5 L and FACT-Lym. The trial employs an innovative Bayesian design with a target sample size of 284 patients: 95 in the ICT arm and 189 in the novel therapy arms. Discussion:Whilst there are many promising novel drugs in early clinical development for rrFL, understanding the relative efficacy and safety of these agents, and their place in modern treatment pathways, is limited by a lack of randomised trials and dearth of published outcomes for standard regimens to act as historic controls. Therefore, the aim of REFRACT is to provide an efficient platform to evaluate novel agents against standard therapies for rrFL. The adaptive Bayesian power prior methodology design will minimise patient numbers and accelerate trial delivery. Trial registration: ClinicalTrials.gov: NCT05848765; 08-May-2023. EudraCT: 2022-000677-75; 10-Feb-2022

Alterations in PGC1[alfa] expression levels are involved in colorectal cancer risk: a qualitative systematic review

Background: Colorectal cancer (CRC) is a major global public health problem and the second leading cause of cancer-related death. Mitochondrial dysfunction has long been suspected to be involved in this type of tumorigenesis, as supported by an accumulating body of research evidence. However, little is known about how mitochondrial alterations contribute to tumorigenesis. Mitochondrial biogenesis is a fundamental cellular process required to maintain functional mitochondria and as an adaptive mechanism in response to changing energy requirements. Mitochondrial biogenesis is regulated by peroxisome proliferator-activated receptor gamma coactivator 1-? (PPARGC1A or PGC1?). In this paper, we report a systematic review to summarize current evidence on the role of PGC1? in the initiation and progression of CRC. The aim is to provide a basis for more comprehensive research. Methods: The literature search, data extraction and quality assessment were performed according to the document Guidance on the Conduct of Narrative Synthesis in Systematic Reviews and the PRISMA declaration. Results: The studies included in this review aimed to evaluate whether increased or decreased PGC1? expression affects the development of CRC. Each article proposes a possible molecular mechanism of action and we create two concept maps. Conclusion: Our systematic review indicates that altered expression of PGC1? modifies CRC risk. Most studies showed that overexpression of this gene increases CRC risk, while some studies indicated that lower than normal expression levels could increase CRC risk. Thus, various authors propose PGC1? as a good candidate molecular target for cancer therapy. Reducing expression of this gene could help to reduce risk or progression of CRC

Atlas of group A streptococcal vaccine candidates compiled using large-scale comparative genomics.

Group A Streptococcus (GAS; Streptococcus pyogenes) is a bacterial pathogen for which a commercial vaccine for humans is not available. Employing the advantages of high-throughput DNA sequencing technology to vaccine design, we have analyzed 2,083 globally sampled GAS genomes. The global GAS population structure reveals extensive genomic heterogeneity driven by homologous recombination and overlaid with high levels of accessory gene plasticity. We identified the existence of more than 290 clinically associated genomic phylogroups across 22 countries, highlighting challenges in designing vaccines of global utility. To determine vaccine candidate coverage, we investigated all of the previously described GAS candidate antigens for gene carriage and gene sequence heterogeneity. Only 15 of 28 vaccine antigen candidates were found to have both low naturally occurring sequence variation and high (>99%) coverage across this diverse GAS population. This technological platform for vaccine coverage determination is equally applicable to prospective GAS vaccine antigens identified in future studies

The development of a decision aid to support Hodgkin lymphoma survivors considering lung cancer screening

BACKGROUND: Decisions aids (DA) can support patients to make informed decisions about screening tests. This study describes the development and initial evaluation of a lung cancer screening (LCS) DA targeted towards survivors of Hodgkin lymphoma (HL). METHODS: A prototype decision aid booklet was developed and subsequently reviewed by a steering group who provided feedback. Revisions were made to produce the DA tested in this study. HL survivors were recruited to an online survey and/or focus groups. Lymphoma practitioners were invited to an interview study. In the online survey, decisional conflict scales and knowledge scales were completed before and after accessing the DA. The focus groups and interviews explored acceptability and comprehensibility and the decisional needs of stakeholders. Focus groups and interviews were audio recorded. The framework method was used to analyse qualitative data. RESULTS: 38 HL survivors completed the online survey. Following exposure to the DA, knowledge of LCS and risk factors and decisional conflict scores (total score and subscale scores) improved significantly. 11 HL survivors took part in two focus groups (n = 5 and n = 6) and 11 practitioners were interviewed. Focus group and interview results: The language, format and length were considered acceptable. Both groups felt the DA was balanced and presented a choice. Icon arrays were felt to aid comprehension of absolute risk values and for some survivors, they reduced affective risk perceptions. Among survivors, the impact of radiation risk on decision making varied according to gender and screening interval, whilst practitioners did not anticipate it to be a major concern for patients. Both groups expressed that a screening offer could mitigate anxiety about lung cancer risk. As anticipated by practitioners, survivors expressed a desire to seek advice from their clinical team. Practitioners thought the DA would meet their informational needs regarding LCS  when supporting survivors. CONCLUSIONS: The DA is considered acceptable by HL survivors and practitioners. The DA reduces decisional conflict and improves knowledge in HL survivors, suggesting that it would support HL survivors to make informed decisions when considering LCS in a future clinical trial. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12911-022-01768-y

Example patient information sheet for a study site for 'Patient views and experiences of preparatory information for CAR-T therapy in England: a qualitative study.'

This link contains the patient information sheet used at the one research site in the study, The Manchester Royal Infirmary (MRI), Manchester University NHS Foundation Trust, at the time of patients in the study being treated with CAR-T cell therapy. A further patent information sheet for the second site, The Christie NHS Foundation Trust, is provided in the text of the manuscript for review. The document Manchester Royal Infirmary CAR-T therapy PIS is shared with permission from the copyright owner under the specified licence

Investigator choice of standard therapy versus sequential novel therapy arms in the treatment of relapsed follicular lymphoma (REFRACT):study protocol for a multi-centre, open-label, randomised, phase II platform trial

Background: Relapsed or refractory follicular lymphoma (rrFL) is an incurable disease associated with shorter remissions and survival after each line of standard therapy. Many promising novel, chemotherapy-free therapies are in development, but few are licensed as their role in current treatment pathways is poorly defined. Methods: The REFRACT trial is an investigator-initiated, UK National Cancer Research Institute, open-label, multi-centre, randomised phase II platform trial aimed at accelerating clinical development of novel therapies by addressing evidence gaps. The first of the three sequential novel therapy arms is epcoritamab plus lenalidomide, to be compared with investigator choice standard therapy (ICT). Patients aged 18 years or older with biopsy proven relapsed or refractory CD20 positive, grade 1-3a follicular lymphoma and assessable disease by PET-CT are eligible. The primary outcome is complete metabolic response by PET-CT at 24 weeks using the Deauville 5-point scale and Lugano 2014 criteria. Secondary outcomes include overall metabolic response, progression-free survival, overall survival, duration of response, and quality of life assessed by EQ-5D-5 L and FACT-Lym. The trial employs an innovative Bayesian design with a target sample size of 284 patients: 95 in the ICT arm and 189 in the novel therapy arms. Discussion: Whilst there are many promising novel drugs in early clinical development for rrFL, understanding the relative efficacy and safety of these agents, and their place in modern treatment pathways, is limited by a lack of randomised trials and dearth of published outcomes for standard regimens to act as historic controls. Therefore, the aim of REFRACT is to provide an efficient platform to evaluate novel agents against standard therapies for rrFL. The adaptive Bayesian power prior methodology design will minimise patient numbers and accelerate trial delivery. Trial registration: ClinicalTrials.gov: NCT05848765; 08-May-2023. EudraCT: 2022-000677-75; 10-Feb-2022.</p