S. Williamson, Kentucky

Imperial Prostate 7 - Prostate Assessment Using Comparative Interventions - Fast Mri and Image-fusion for Cancer

Background and study aims: The aim of this study is to improve the way prostate cancer is diagnosed by looking at two different types of MRI scans and two different types of prostate biopsy (tissue samples). A large study such as this is required to help the NHS decide how to diagnose prostate cancer in the future. If a person is suspected of having prostate cancer, then they are referred by their GP. At the hospital clinic, the participant will then have an MRI scan. If this scan shows that cancer might be present, then the doctor will usually suggest that the patient has a biopsy. There are two ways of doing a prostate MRI. One takes 30-40 minutes and requires a contrast injection called gadolinium (like a dye). This is called long MRI and is most commonly used in the NHS. Gadolinium is safe as it rarely causes any bad reaction but using it means that the scan takes more time. Another type of MRI takes 15-20 minutes and does not use gadolinium contrast. This is called a short MRI. Many studies over the last 5 years have shown that the long and short MRIs are similar in their accuracy in diagnosing important prostate cancer. These studies have not been of high quality or large enough to change NHS practice. Patients with suspicious areas on the MRI are usually advised to have a prostate biopsy. This involves taking tissue samples using a needle. The samples are then looked at under the microscope by a pathologist to see if cancer cells are present. There are two ways of doing a prostate biopsy. One is where the person doing the biopsy decides where to put the biopsy needle by looking at the MRI scans that have been already taken on a computer screen. The needle is guided to the prostate using live ultrasound scans that are shown on a different screen near the patient. The biopsy operator makes a judgement about where to place the biopsy needles. This is called visual registration. Tissue samples from other areas of the prostate that look normal on the MRI scans are also taken to ensure cancer is not missed. The other type of biopsy is called image fusion. During image fusion biopsy, the biopsy operator uses the MRI scans that have been taken beforehand but laid on top of the live ultrasound images during the biopsy. This uses software and takes a few minutes longer to perform. Once the MRI images and ultrasound images are 'fused', the actual biopsies are taken as normal. Studies over the last 5 years have shown mixed results. Some have shown that image fusion biopsy is no better than visual registration biopsy, whilst a few have shown it might make a difference in improving cancer detection. As a result, it is not known for certain which way is better. A large study is needed to show whether the investigators need to do image fusion or not, in order for the NHS to decide whether or not to use it in all hospitals doing prostate biopsies.

Reconstruction in Extended MArgin Cancer Surgery

This is an observational multicentre retrospective and prospective cohort study, and a qualitative study. The project will have three working packages: - Work package 1 - maintenance of a colorectal surgery database - Work package 2 - prospective collaborative national UK study - Work package 3 - qualitative analysis with semi-structured interviews WORK PACKAGE 1 - COLORECTAL SURGERY DATABASE: Data collected includes: - Basic demographic information - Co-morbidities at time of surgery - Other cancer treatments - Final cancer staging and diagnosis - Type of procedure - Methods of reconstruction - Use of healthcare resource: (theatre time, surgical teams, use of consumables, index operation intensive care stay, total length of stay, planned or emergency readmissions, use of imaging for complications, re-interventions, and outpatient clinic use). - Morbidity - empty pelvis syndrome complications with collation of all complications that occurred summarised into: (the highest Clavien-Dindo (CD) score, and the comprehensive complication index by accumulating CD graded complications that a patient has as a result of their surgery. - Survival: overall and disease-free survival - Patient reported outcome measures Any other routinely collected clinical data will be included. Of particular mention we will include and analyse Cardiopulmonary exercise testing data, data derived from the perioperative medicine screening and assessment, data derived from prehabilitation, radiomic data e.g. muscle/fat structure and function derived from CT, MRI or PET-CT. WORK PACKAGE 2 - PROSPECTIVE COLLABORATIVE STUDY: Abdominoperineal excision and pelvic exenteration can be used in a wide range of cancer types, and in the case of pelvic exenteration can be used to manage both recurrent and primary cancers. The principal PROM used will be the EORTC QLQ-C30 with its modular questionnaires giving additional insight into disease-specific quality of life. All amendments have been made in line with NIHR RfPB funding received in November 2024. Patients will be recruited once a decision to undertake abdominoperineal excision or pelvic exenteration surgery has taken place. Participants will be sent a participant information sheet which will include the dates of when participants can expect follow up telephone calls, with information on how to contact the study team to change these should participants wish to. Once consented participants will undergo the following PROMs as part of their baseline questionnaire: - EORTC QLQ-C30 with specific cancer-type modules - EQ-5D-5L - LRRC QoL - Decision Regret - Comprehensive Score for Financial Toxicity (COST), financial status questionnaire (non-validated) and Patient employment status questionnaires. The investigators anticipate that participants will be able to self-assess the above PROMs on a paper printed form, however a member of the research team will be available to support the participant if required. Clinical information will also be collected pre-operatively, including: demographic information, co-morbidities, cancer staging, and previous cancer treatments. Patients will be given copies of the follow up questionnaires at this time so participants have them as a reference when completing follow up questionnaires. Patients can opt for either email or telephone follow up for quality of life, if opting for email REDCap study will automatically send out emails based on the date of surgery. The patient will then undergo their surgery with method of reconstruction at the discretion of the operating surgeon(s). Following the index admission researchers will enter details on the hospital stay: - Type of procedure - Methods of reconstruction - Theatre time - Theatre teams - Use of consumables - Length of intensive care and hospital stay - Use of imaging for complications - Re-interventions for complications - Discharge destination following index admission - Final cancer staging and other pathological outcomes. - Perineal and empty pelvis morbidity, and overall Clavien-Dindo and Comprehensive Complication Index - NHS healthcare utilisation costs - If applicable survival and cause of death At 3 months post-operatively questionnaires will be repeated over the telephone including: - EORTC QLQ-C30 with cancer-specific module - EQ-5D-5L - LRRC QoL - Decision Regret - Comprehensive Score for Financial Toxicity (COST), Patient reported heath resource utilisation and NHS healthcare utilisation costs. At this same time point researchers will review routinely collected clinical data and use of in-hospital health resources to include: - In-hospital health resource use: planned or emergency re-admissions, use of imaging to investigate complications, re-interventions (surgical and radiological), planned or unplanned outpatient visits. - Longitudinal CCI scores updated, and if applicable an increase in CD if a more severe complication develops. - If applicable cancer recurrence, survival and cause of death will be recorded. Patients will be emailed or telephoned on the date specified on their participant information sheet, however if this time is not convenient then a better time will be arranged with the patient. If participants do not respond to the email or first telephone call then the investigators will make a further three separate attempts to contact the patient. If there is still no response participants will be deemed lost to the study. This follow up process will be repeated again at 6 months and 12 months. At the 12 month time point the investigators will ask patients additional questions on their use of health care resources and their current financial status, to include: - Use of community health resource use due to complications including: GP appointments and nursing home care days required for recovery from surgery. - Use of healthcare resources at hospitals other than the treating hospital - clinic appointments and admissions At the end of this time the patient will have completed the study. WORK PACKAGE 3 - QUALITATIVE STUDY: The qualitative study will recruit patients from work packages 1 and 2. The investigators will invite 30 purposefully sampled patients that are 3 months following their surgery. Suitable patients will be contacted with a posted participant information sheet and a telephone follow up call to allow participants to ask questions about the study. Following informed consent semi-structured interviews will take place with semi-structured open questions to guide the discussions. Interviews will be recorded on an encrypted audiorecorder and then transcribed. The investigators will initially undertake three pilot interviews to review that the semi-structured interview schedule is adequate to fully explore our objectives and to obtain good quality interview transcripts for analysis. These pilot interviews once completed will be reviewed by the research team. The semi-structured interview schedule questions may be changed if the interviews are of poor quality, pilot interviews demonstrate new insights from participants that suggest fruitful lines of enquiry, or inconsistencies that require further exploration. If subsequent interviews are very different than the pilot interviews following these changes, then these early interviews will not be included in the qualitative analysis and additional patients will be recruited. Patients recruited at 3-months following surgery will be offered a repeat interview at 12-months following their surgery DATA ANALYSIS PLAN: Statistical analysis: The investigators will be collecting data on the timepoints as described above. Continuous data will be will be summarised using descriptive statistics (mean, median, standard deviation, lower and upper quartiles). Categorical data will be summarised using counts and percentages. As studies are non-randomised, the investigators will utilise regression models and principal component analysis to adjust for confounding in this observational study. In order to obtain our outcomes a brief summary of analyses is below. Work package 1 (Colorectal Database): Primary analysis: - Frequency of morbidity relating to the empty pelvis syndrome and perineal wound will be compared for different types of perineal reconstruction will be analysed using multiple linear regression. Secondary analysis: - Overall morbidity will be obtained using highest CD scores for different methods of perineal reconstruction analysed using multiple linear regression. - Disease free and overall survival will be analysed using Kaplan-Meier curves and log rank tests with a multivariate Cox regression hazard model to identify factors independently associated with survival, including method of reconstruction. Exploratory analysis: - Other factors including age, gender, BMI, final staging, co-morbidities, type of operation, neoadjuvant chemoradiotherapy and use of intra-operative electron radiotherapy will be included in the analysis - Other outcomes including primary operation time, lengths of stay, and readmissions will be explored Work package 2 (prospective study): Primary and secondary analysis: - Patient reported outcome measures will be analysed using regression models, including linear mixed-effects models for repeat measures and adjusted analyses. - The same clinical data fields will be collected as per work package 1, the analysis above repeated with exploratory analysis to find factors that are independently significantly associated with changes in the PROMs. Health economic analysis: Work package 1 (retrospective study): The investigators will collect data on use of hospital healthcare resources in each patient group. The investigators will collect resource use for each parameter required for each patient. The investigators will then undertake costing using a micro-costing approach and health resource group costing for each parameter. Applying costs to each parameter will use a combination of manufacturer prices for consumables, National Cost Collection for the NHS, National Schedule of NHS Costs, NHS National Tariff and the Unit Costs of Health and Social Care from the Personal Social Services Research Unit. The investigators will then report overall costs associated with different methods of perineal reconstruction and the cost of complications that were encountered. Work package 2 (prospective study): The investigators will collect hospital healthcare resource use data prospectively and apply micro-costing to these parameters in the same way as per work package 1 for each patient and their method of reconstruction. The investigators will also ask patients to provide us with use of community healthcare resources as a result of their surgery, data for which the investigators will not be able to obtain from their clinical notes. Participants will receive EQ-5D-5L and EORTC QLQ-C30 questionnaires at baseline, 3 months, 6 months and 12 months. From these responses the investigators will map onto EQ-5D-3L in order to reduce the overall number of questionnaires patients are undertaking in our study. This will allow us to plot EQ-5D-3L responses for different methods of reconstruction and plot the area under the curve. Within the trial time a health economic model would be built which would follow the NICE reference case and ISPOR Task Force guidelines on health economic analysis. This will enable us to present Quality Adjusted Life Years and incremental cost-effective ratios for the different methods of perineal reconstruction. Qualitative analysis: Audio transcription will be transcribed verbatim, checked against the recording and anonymised. Data will be uploaded to NVivo for data management. Preliminary summaries will be written after each interview to identify emerging themes to follow-up discussions. The follow-up interview will ask patients to reflect on the content of their previous interview and discuss any changes. Longitudinal interview analyses will use constant comparative methods from grounded theory and data coded using NVivo's framework matrix facility to examine themes longitudinally, enabling comparisons within each case and across cases, focusing on changes over time. The stages of data analysis, drawing on longitudinal comparisons, will include: 1. Initial reading: Review interview data. 2. Preliminary coding: Two researchers code the data. 3. Team meeting: Discuss and refine codes with wider research/PPI team. 4. Individual Case Coding: Code all interview data for each participant. 5. Categorising Codes: Group codes into categories for each case. 6. Longitudinal comparisons: Within case and category comparisons focussing on changes over time. 7. Focused coding: Examine categories in relation to emerging concepts and phases. 8. Discussion on Themes: PPI co-led focus group discussions of final themes. 9. Development and Dissemination: Report write up are dissemination. Based on an iterative process, emerging themes will be used to develop explanatory accounts. Analysis will draw on sociological perspectives of illness adaptation, recovery and self-management in addition to psychological theories of individual behaviour change. All qualitative and quantitative data will inform 3 patient focus groups, where PPI and charity collaborators along with 5 newly trained PPI members will discuss data analyses from a patient perspective, contributing to initial discussions around developing a patient decision aid.

Repurposed Drugs to Improve Haematological Responses in Myelodysplastic Syndromes

Study of OCTAPLEX in Patients With Acute Major Bleeding on DOAC Therapy With Factor Xa Inhibitor

Frailty and Sarcopenia Outcomes in Emergency General Surgery

Frailty has a significant impact on surgical outcomes. It is an independent risk factor for adverse outcomes following surgery including complications, length of stay, inability to return home and mortality. Frailty is a physiological decline across multiple body systems accumulating in loss of reserves and increased vulnerability to stressors. Sarcopenia, loss of muscle mass or progressive reduction in muscle mass, is one of the central physiological manifestations of frailty resulting in weight loss, weakness and exhaustion. Frailty has both a strong correlation with age as well as significant overlap with disability and co-morbidity. Further factors strongly influencing outcome, 30 day and mortality have been described including polypharmacy, Charlson co-morbidity index, age, not independently mobile, emergency admission and falls. It has been recognised that poor outcomes are multimodal relating to the interplay of co-morbidities, physical functioning and nutrition. Assessing frailty can be completed using simple questionnaire tools, as well as more complex assessment of co-morbidity, functional status, and disability. There is good evidence the simple tools can be as accurate as formal geriatric assessments. As sarcopenia relates directly to many manifestations of frailty it can be used as a surrogate marker. One of the favoured ways for diagnosing sarcopenia is using CT morphometric biological markers. This uses an axial image at the level of the 3rd lumbar vertebra (L3) to assess the total or cross-sectional volume of the psoas muscle, giving rise to indices measuring muscle mass, visceral adipose tissue and subcutaneous adipose tissue. Major abdominal emergency surgery is a high-risk procedure with ongoing audit and outcome monitoring. Currently data collection for UK National Emergency Laparotomy Audit (NELA) is in its fourth year with annual reports into the management and outcomes of emergency laparotomies. Observation and audit of these outcomes remain central to improving service and healthcare both regionally and nationally. Furthermore, this group of patients is not well represented in research and is one of the most understudied surgical cohorts that exist. This is especially the case for patients presenting with an acute surgical diagnosis and are deemed unable to withstand the stress of surgery, and hence pursue a conservative or radiological treatment option. With our ageing, co-morbid population this is becoming increasing common. The diagnosis of frailty and sarcopenia are a significant measurable and modifiable risk factor that impacts on perioperative surgical care, healthcare provider and patient decision-making and most importantly long and short term outcomes. This urgently requires further audit and study. Work package one (WP1): Retrospective scoping cohort study in acute general surgery Patient identification The number of patients recruited from each participating hospital will be proportionate to the total number of cases, in accordance with relative annual case volumes (as reported by NELA - in the case of less than 100% case capture, the theoretical 100% case number will be used). This will provide a representative sample of the recruiting region's population. The most recent laparotomy cases with 1-year follow-up mortality data available will be included at the time of study activation. Data collection over a predicted six week period will be undertaken or until the sample size is reached. Retrospective collection of routinely recorded clinical data will be performed (See appendix data collection tool). This includes, but is not restricted to [a] routine clinical variables: patient characteristics, demographic, pathological and physiological variables will be captured in line with NELA data, alongside confounding factors associated with frailty and sarcopenia. Protocol for measuring muscle radiation attenuation Inclusion: Retrievable CT abdomen/pelvis on an electronic NHS PACS system. CT can be non-contrast or with contrast, supine or prone but must be of sufficient quality for the sarcopenia CT analyses software to handle (Slico-matic™, TomoVision, Magog, Canada ). Exclusion: CT-scans with large radiation artefacts or with missing parts of muscle tissue on the ventral, dorsal, or both lateral edges of the scan preventing sarcopenia assessment. Patients meeting inclusion criteria will have their CT extracted and reviewed by a trained independent party. This may through an allocated representative at the base hospital or the CT can be extracted and sent in a fully anonymised format to the central unit for sarcopenia assessment. CT scans obtained via a PACS system can up transferred through secure inter-hospital PACS transfer. Those with non-compatible systems can either be uploaded via CD or analysed at the data collection site. The outcome of the assessment for sarcopenia will define whether a patient is considered to have sarcopenia. Participants can be identified primarily from the NELA database with confirmation of GI pathology on the radiological report. This can be cross reference against admission logs, acute surgery admission databases, theatre logs for emergency surgery and NELA databases to maximise case capture. Once patients are confirmed to meet the inclusion criteria their data can be gathered into a data collection tool. The CT scan will be extracted and sent for analysis. All patients meeting inclusion criteria will be identified by the lead researcher in each centre. Frailty scores are already part of standard acute admission clerking proformas in many of the hospitals across the region; as such the researcher's role will be ensure appropriate and complete data capture from existing clinical information sources, but no additional intervention or questioning of patients beyond current standard of care will be required. Patients will be collected across a set time scale as listed above. Baseline demographics and disease factors will be collected as per collection proforma attached as supplementary material. The Reported Edmonton Frail Scale (REFS) is collected at time of admission as part of routine clinical assessment for surgical admissions. This is a validated, self-reported patient questionnaire that can categorise the degree of frailty. This information is routinely collected in many acute unit or care of the elderly departments. The REFS will enable a consistent method of collecting this data utilising a rapid and well validated tool. For patients presenting in extremis or unable to complete the score due to an acute state or requirement for prompt treatment, this will be gathered at the next appropriate pre-operative opportunity. Patients unable to complete a REFS given the best opportunity will be excluded, however reasons for exclusion will be recorded.

Myeloma XIV: Frailty-adjusted Therapy in Transplant Non-Eligible Patients With Newly Diagnosed Multiple Myeloma

The Role of Ixazomib in Autologous Stem Cell Transplant in Relapsed Myeloma - Myeloma XII (ACCoRd)

Assessment of HydroxyColl Bone Graft Substitute in High Tibial Osteotomy Wedge Grafting.

Osteoarthritis (OA) of the knee is joint damage, resulting in pain accompanied by varying degrees of functional limitation and reduced quality of life. 20% of adults over 50 and 40% over 80 years report disability from knee pain secondary to osteoarthritis.The majority of patients present to primary care with symptoms of pain and stiffness, which reduces mobility and with associated reduction in quality of life, with many patients not requiring surgery, with their symptoms adequately controlled by non-surgical measures. When patient's symptoms are not controlled by up to 3 months of non-operative treatment they become candidates for assessment for joint surgery. There are a number of surgical (Arthroscopy, Total/Partial Knee Replacement, High Tibial Osteotomy) and non-surgical (including exercise, weight loss, manual therapy, oral medication, injection therapy, splints and braces) options available. The decision to undergo surgery is based on patient symptom pattern, with the type of surgery determined by the pattern of joint damage and the patient's preference. High Tibial Osteotomy (HTO) should be considered primarily for patients with varus mis-alignment in medial unicompartmental osteoarthritis of the knee as the main indication for the procedure. HTO involves removing or adding bone to realign the limb and offload the knee. It is effective and can provide functional outcomes similar to those seen after joint replacement. HTO is a commonly used surgical procedure and has wide appeal because of the preservation of the knee joint. The principal advantages of opening wedge high tibial osteotomy include maintenance of the bone stock, correction of the deformity close to its origin, and no requirement for a fibular osteotomy. Although it is a good option for young patients with isolated medial compartment OA and varus deformity, it can be done even for older active people over 65. By preserving the patient's own knee anatomy, a successful osteotomy may delay the need for a joint replacement for several years. Another advantage is that there are no restrictions on physical activities after an osteotomy, even high impact exercise. Contemporary Surgical approaches to HTO can often utilise bone graft substitutes to improve patient outcomes. Bone grafting in open wedge high tibial osteotomy (HTO) is an area of clinical research that requires further evaluation. While open wedge high tibial osteotomy (OWHTO) with medial plate fixation is a proven adequate and safe method for treatment of medial compartment osteoarthritis of the knee and varus deformity, particularly in young and/or active, it nevertheless creates a gap in the metaphysis of the tibia. To enhance bone healing and increase initial mechanical stability, a high degree HTO may require the application of bone graft/substitute to fill the osteotomy gap. Moreover, HTO has been associated with risk of nonunion, collapse and loss of correction. Autologous bone graft is the "gold standard" to fill the bone defect, but iliac crest graft harvest has risks. The associated complications include pain, thigh hypoesthesia, infection, pelvic bone fracture and discomfort wearing clothes. Allograft is commonly used to avoid the risks of autografting, such as donor side morbidity. However, the use of allograft increases additional risks such as disease transmission, immunologic reactions and slow remodelling. Due to the limited autologous bone availability and the problem of donor-site morbidity, many efforts have been made to find adequate supporting material for augmentation after osteotomy. Hydroxyapatite, β-tricalcium phosphate or the combination of both are the most commonly used synthetic augments in HTO. However, the most suitable material for filling the opening space in OWHTO has not been conclusively identified. While HTO with and without bone grafting has been assessed as radiologically equivalent, of particular interest to clinicians and patients is the contention around the secondary outcomes (site morbidity and bleeding, chronic pain, patient discomfort long term) which are frequently a challenge in postoperative management of patients. Autologous bone graft would still be the best choice for a lot of applications where bone grafting is needed but there are many disadvantages - the relatively high donor morbidity and the limited amount which can be harvested - which will eventually lead to a very restricted use of it. Allografts do not have these limitations, but in the form of demineralized bone matrix they have very variable osteoinductive properties and can possibly transmit diseases. Synthetic 2nd generation biomaterials have a long and safe history of use but do not provide a compelling alternative to traditional bone grafting. 3rd generation biomaterials as bone graft substitutes, such as HydroxyColl, offer exciting prospects of improved patient clinical outcomes and may provide a viable alternative to autologous bone grafts. Treatment for these patients would be with Open Wedge High Tibial Osteotomy with medial plate fixation. Over the period of the trial, adverse events will be reported by the study centre and it will be the prominence or absence of these, along with blood inflammatory marker evaluations that will determine the inherent safety of Hydroxycoll compared to the standard of care. At each follow up visit x-rays will be performed and evaluated by a certified radiologist. Site morbidity and bleeding will be clinically assessed. They will report and assess the radiographic images determining if healing has occurred. Along with the clinical assessment, the surgeon or a member of the clinical team will determine extent of healing. Patients will also self-report a number of key pain, mobility and post-operative joint inflammation outcomes. The study is a single centre randomized blinded study to assess the efficacy and safety of Hydroxycoll bone graft substitute used as a bone graft substitute in Open Wedge High Tibial Osteotomy with DePuy Synthes TomoFix Medial High Tibial Plate (MHT) fixation (Standard of Care). This study has been designed to last for 52 weeks with follow up visits post surgery, 6 weeks, 12 weeks and a final follow-up at 52 weeks. In case of AEs/SAEs ongoing when the patient has completed the study, the patient will be contacted by phone one month after study completion for follow-up. The study will have 2 arms with 20 subjects per arm, each receiving at the time of surgical intervention either; 1) Open Wedge High Tibial Osteotomy with medial plate fixation (without bone grafting). 2) Open Wedge High Tibial Osteotomy with medial plate fixation (with bone grafting) using Hydroxycoll bone graft substitute. An Independent Review Board (IRB) will approve the protocol before the study begins. A clinical monitor selected by SurgaColl will monitor the trial. Any serious adverse events (SAE) will be reported as soon as possible (within 48 hours of awareness) to SurgaColl by the study centre. SurgaColl will communicate the SAE to all relevant authorities.

ATTUNE® Revision- Complex Primary in Total Knee Arthroplasty Population

Within primary TKA, there are factors that lead to more complex procedures that include patients with high BMIs, advanced preoperative deformities and ligamentous laxity. Such cases may require the surgeon to treat using ancillary components, such as stems and/or augments and/or additional constraint. This post-market study will evaluate the short/medium term clinical performance and medium term survivorship of the ATTUNE Revision system system, which includes instrumentation, in complex primary TKA. The study is designed as a worldwide non-comparative, multi-center study with each site initially having a cohort of approximately 20 Subjects to recruit. The study will enroll approximately 200 fixed bearing and approximately 200 rotating platform configurations. The 2-year KOOS-ADL (activities of daily living) was selected as the primary endpoint because it will evaluate the post-operative period during which outcomes typically plateau and will therefore provide a good indication of longer term outcomes Male and female Subjects, age 22-80 years, inclusive, who require a primary knee arthroplasty in a joint that, due to deformity, instability, bone loss etc., necessitates the use of implants found within the ATTUNE Revision knee system and are suitable candidates for TKA using the ATTUNE® Revision system are eligible for enrollment in this study.

Platinum and Polyadenosine 5'Diphosphoribose Polymerisation Inhibitor for Neoadjuvant Treatment of Triple Negative Breast Cancer and/or Germline BRCA Positive Breast Cancer

Randomised, phase II/III 3 stage trial to evaluate the safety and efficacy of the addition of olaparib to platinum-based neoadjuvant chemotherapy in breast cancer patients with TNBC and/or gBRCA. Disease under investigation: Breast Cancer Purpose of clinical trial: To establish if the addition of olaparib to neoadjuvant platinum-based chemotherapy for Triple Negative Breast Cancer (TNBC) and/or germline BRCA (gBRCA) breast cancer is safe and improves efficacy. Trial Design: Open label, randomised, 3-stage Phase II/III Sample Size: Minimum of 780 patients (including at least 220 gBRCA patients equally allocated to the control and the selected research arm). Non Investigational Medicinal Products: Prophylactic granulocyte-colony stimulating factor (G-CSF) to be given as per local practice and 3 cycles of anthracyclines as per local practice. Treatment period: A minimum of 21 weeks of chemotherapy followed by surgery. Procedures: Screening & enrolment Eligible patients with early breast cancer will be registered and consented for screening: BRCA mutation test Tumour Infiltrating Lymphocytes(TILs) score Cytokeratin 5/6 (CK5/6), Epidermal Growth Factor Receptor (EGFR) +/-, Androgen Receptor (AR) status by Immunohistochemistry (IHC). Standard assessment prior to chemotherapy Standard staging to exclude metastatic disease. When eligibility is confirmed, patients will be randomised via a web-based central system which will allocate each patient a unique randomisation number associated with one of the treatment arms. PARTNERing Pathway - For those patients who still have residual disease after receiving neoadjuvant chemotherapy +/- olaparib there is the opportunity to be screened to a sub-study to receive a further two cycles of chemotherapy consisting of Duralumab and AZD6738. End of Trial: For patients, the end of trial is after the last follow-up visit or contact with the research team planned 10 years after surgery. Procedures for safety monitoring during trial: Pharmacovigilance will be performed by the PARTNER Trial Office. Also, the Trial Management Group and the Independent Data and Safety Monitoring Committee will regularly review the patient safety data. Criteria for discontinuation of trial treatment on safety grounds: Severe toxicity or inter-current illness, requiring cessation in the judgement of patient's clinician. Patient within 4 weeks has not recovered from toxicity to an extent that allows further treatment. Patient unable to comply with trial procedures. Disease progression while on trial treatment. Patient becomes pregnant.