Chanceaux Sur Choisi, France

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

Tracking Mutations in Cell Free Tumour DNA to Predict Relapse in Early Colorectal Cancer

TRACC Part B: Despite potentially curative surgery +/- adjuvant chemotherapy, a proportional of patients with early stage CRC will experience disease relapse. Current tools for surveillance, e.g., blood sampling for tumour markers (CEA) are neither sensitive nor specific. We hypothesise that detection of mutations in circulating free DNA (cfDNA) in plasma can predict relapse in patients with early stage CRC. Circulating cell free tumour DNA (ctDNA) maintains the same mutations that are present in tumour. In colorectal cancer CRC, primary tumours and& metastases exhibit high genomic concordance. Therefore the TRACC study TRACC Part B is investigating whether serial blood samples taken from in patients with stage II and III fully resected early stage CRC colorectal cancer that have undergone potentially curative surgery, blood samples to can be used to detect and& quantify ctDNA may in order to identify minimal residual disease MRD and predict relapse earlier than existing methods. CtDNA may ultimately help identify a subset of patients that are or are unlikely to benefit from adjuvant chemotherapy and could therefore safely spare some patients from receiving unnecessary chemotherapy & its associated side-effects. TRACC Part C: We hypothesis that ctDNA guided adjuvant chemotherapy administration will enable biomarker driven selection of patients who would and would not benefit from adjuvant chemotherapy and thereby reduce the proportion of patient receiving unnecessary adjuvant chemotherapy, reducing the potential side effects associated with it, but without compromising disease free survival (DFS). : This part of the study will use tThe blood test ctDNA result from a post-operative blood sample willto guide adjuvant chemotherapy treatment decisions. The study aims to demonstrate that athe de -escalation strategy of ctDNA guided adjuvant chemotherapy is non-inferior to standard of care treatment as measured by 3 year DFS in patients with high risk stage II and stage III CRC, in those who have no evidence of MRD (ctDNA negative). after surgery for patients with colorectal cancer who are following the standard of care pathway. Patients are randomised at the post- operative time point to: Arm A (standard of care adjuvant chemotherapy), or Arm B (ctDNA guided adjuvant chemotherapy) arm. For the ct DNA guided arm, patients who are ctDNA negative at this time point will have their chemotherapy de-escalated.

Naloxone HCl PR Tablets in Patients With Opioid Induced Constipation

A Randomised Open-label Phase III Trial of REduced Frequency Pembrolizumab immuNothErapy for First-line Treatment of Patients With Advanced Non-small Cell Lung Cancer (NSCLC)

Immunotherapy with pembrolizumab targeting the T cell inhibitory PD-1 receptor has significantly improved outcomes in advanced non-small cell lung cancer (NSCLC). Approximately 3600 new patients are treated in the 1st line setting per year in England alone and up to 25% remain on 6 weekly pembrolizumab for 2 years. However, pharmacological and clinical trial data suggest current frequent dosing for 2 years result in overtreatment. Indeed, pembrolizumab remains bound to its target receptor for up to 100 days following a single dose and studies in multiple tumour types have found no relationship between dose and patient outcome. Moreover, anti-PD1 treated patients who respond but discontinue therapy either as planned after 2 years, or earlier because of toxicity, can either remain in remission and/or be sensitive to re-challenge with pembrolizumab. REFINE-lung will test whether reduced pembrolizumab dose frequency (9, 12, 15, 18 weeks) after 6 months of standard treatment is safe and effective. This UK study represents a unique opportunity to determine whether pembrolizumab dose frequency can be safely reduced in NSCLC, resulting in significant cost benefits to the NHS and globally, in addition to enhanced patient QoL associated with fewer hospital attendances and reduced toxicity.

EXTENDed Antibiotic Durations Compared to Standard Durations for Patients With Complicated Intra-abdominal Infection.

UK data suggests that current treatment for complicated intra-abdominal infections (cIAIs) results in unacceptably high rates of cIAI relapse and extra-abdominal infection. As a guiding rule, shorter antibiotic durations are important to combat antimicrobial resistance, but this is not true when these shorter courses need repeating and result in more days in hospital. Optimal care for patients should be our primary concern. The EXTEND trial aims to find out whether a fixed extended duration of 28 days of antibiotics is superior to the current standard duration (typically 7-18 days) based on clinical outcomes and quality of life assessed over 180 days of follow up. Cost effectiveness will also be determined. A target of 1166 patients will be recruited from ICUs and hospital in-patient wards across approximately 30 NHS trust hospitals. Only patients that are able provide consent (or those with a consultee able to confirm whether the patient would wish to be included in the study) can take part in the trial. They will receive antibiotics as prescribed by their treating clinician, but the duration of treatment will be determined by randomisation. Patients will have equal chance of randomisation to the standard care arm, in which the antibiotic duration will be determined by the treating clinician, or the intervention arm, a fixed duration of 28 days treatment. Patients (or a personal consultee) will complete a quality of life questionnaire at baseline and 30, 60 and 180 days after randomisation. At follow-up timepoints they will also complete questionnaires on antibiotic use and health care resource use. Hospital notes will be used to collect data on inpatient admissions, relapse and further infections. The study is Sponsored by the University of Leeds

Early Vasopressors in Sepsis

Sepsis results from overwhelming reactions to microbial infections where the immune system initiates dysregulated responses that lead to remote organ dysfunction, shock and ultimately death. Sepsis remains a significant global issue - as well as direct mortality, survivors suffer long term reductions in patient centred outcomes, with reduced quality of life and functional status. Patients with hypotension and organ hypoperfusion as a result of sepsis have poorer outcomes by dysregulated inflammation, endothelial dysfunction, immune suppression, and organ dysfunction. Current guidelines highlight the importance of early fluid resuscitation, but the association of early fluid therapy with improved outcomes is unclear. In the resuscitation phase, current practice is to give intravenous (IV) fluid and intermittent vasopressor boluses if required, before, for some patients, continuous vasopressor infusion via a central venous line in Intensive Care (ICU). An alternative, early continuous peripheral vasopressor infusion (PVI) is not routine practice in the UK. Current practice in the UK is guided by NICE Sepsis guidance and the international Surviving Sepsis Campaign (SSC) consensus recommendations. Both specify intravenous fluid administration as a central tenet of early resuscitation of patients with septic shock, with intravenous vasopressor administration recommended after intravenous fluid resuscitation. NICE recommend boluses of 500ml of crystalloid and "refer to critical care for review of management including need for central venous access and initiation of vasopressors". SSC recommend 30ml/kg crystalloid in first hour, followed by vasopressors to maintain MAP>65. The current NICE fluid resuscitation guideline, November 2020, continues to emphasise 500ml boluses of crystalloid as usual care. A recent international survey of 100 critical care and EM physicians regarding intravenous fluid resuscitation practice, confirmed that an initial bolus of 1000ml of crystalloid, followed by 500ml boluses of crystalloid remained the most common management strategy for the initial treatment of septic shock. This persisted despite the lack of benefit demonstrated in three landmark trials of protocolised sepsis management. In recent years, there has been increasing acceptance of peripheral administration of norepinephrine, based on evidence of safety and efficacy. The Intensive Care Society published guidance on peripheral vasopressor infusion in November 2020. We have recently conducted a survey amongst ED and ICU clinicians in the UK regarding attitudes and current practice related to the use of intravenous peripheral vasopressors. Eighty two respondents provided the following answers 1. Experience of use of any intravenous vasopressor in ED was high (81%); 2. Exclusive PVI made up 23% of all vasopressor use in ED; 3. Norepinephrine (norepinephrine) was the most common vasopressor (54%); 4. Barriers to PVI were local protocols and an appropriate level of care in the destination ward for a patient on vasopressor infusion.

Functional and Ultrasound Guided Resection of Glioblastoma

Stage 1 (IDEAL IIB study) of the trial is observational only and all participants will receive all technologies during surgery. Stage 2 will be randomised. Randomisation will be via the web-based service provided by the Oxford Clinical Trials Research Unit (OCTRU), using the method of minimisation. Participants will be randomised 1:1 to either: 1. Standard care surgery (neuronavigation based on preoperative imaging and intraoperative use of 5-ALA)(Control arm) 2. Standard care surgery (neuronavigation based on preoperative imaging and intraoperative use of 5-ALA) AND of DTI neuronavigation and NiUS (Intervention arm) At baseline all participants will undergo a routine preoperative neuronavigation MRI scan. Those participants randomised to the experimental arm, will also have a DTI scan (additional 5 minutes in the MRI). All participants will then undergo the planned resection of their tumour, with the additional technologies if they are in the experimental arm. Following surgery, participants in both arms have the same follow up schedule and undergo standard clinical care for a total of 24 months.

Acalabrutinib in Combination With R-CHOP for Previously Untreated Diffuse Large B-cell Lymphoma (DLBCL)

Diffuse large B-cell lymphoma (DLBCL) is the most common of the non-Hodgkin's lymphomas. Whilst the majority of patients will respond well to conventional treatment (R-CHOP - rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone), a significant number of patients lymphoma will not respond to initial therapy or their disease will return after completion of therapy. In a number of B-cell diseases an enzyme called, Bruton tyrosine kinase (BTK) prevents death of tumour cells, including in DLBCL. Acalabrutinib is an orally active BTK-inhibitor and it is thought that stopping BTK being activated may help in treating B-cell diseases. It is hypothesised that the addition of Acalabrutinib to standard R-CHOP immunochemotherapy may improve outcomes of patients with DLBCL. REMoDL-A is a randomised, phase II, open label, multicentre study that will be open in up to 50 centres. Up to 553 patients (453 randomised) will be recruited. Following informed consent all patients will receive 1 cycle of conventional R-CHOP chemotherapy. At the same time the diagnostic pathology block will be sent for molecular profiling by the Haematological Malignancy Diagnostic Service (HMDS). The delivery of the first cycle of R-CHOP will allow a sufficient interval for real time determination of molecular phenotype. Patients whose biopsies yield sufficient tumour material for profiling will be randomised 2:1 in favour of the experimental arm (R-CHOP + acalabrutinib). The primary objective will be to establish if combining acalabrutinib with R-CHOP improves efficacy, compared to R-CHOP alone, for the treatment of previously untreated patients with DLBCL to a degree that justifies further development of this approach.

Multi-Centre Observational Study of Maintenance Niraparib in Treatment of Ovarian CanceR

This is a multi-centre, observational (non-interventional) study, designed to follow patients with advanced ovarian fallopian tube and primary peritoneal cancer, who are receiving Niraparib as maintenance treatment, according to the Niraparib access criteria (via TESARO patient access programme, EMA licence and NHS pending NICE assessment due 2018) including assessment of tolerability to Niraparib therapy. These pathways will include patients who have been registered and not prescribed drug. In these cases, the reason for patients not receiving Niraparib will be recorded. Up to 16 centres will be involved in the study. Centres will be selected based on interest in or experience of prescribing Niraparib and geographical location in order to give a representative picture of the management of Niraparib in the UK. Cohort 1: Retrospective Cohort This cohort will include: - Patients who have previously commenced maintenance Niraparib prior to the MONITOR study opening at the site and are still receiving Niraparib but in whom quality of life data are not available. - Patients who have previously commenced Niraparib prior to the MONITOR Study opening at the site but are now deceased but will be eligible for retrospective data collection without the need for informed consent. - Patients who have previously commenced maintenance Niraparib prior to the MONITOR study opening at the site but have discontinued treatment. - Data in respect of AEs, SAEs, ADRs and AESIs will be recorded in Case Report Forms and be identified via the patient's medical records. There is no requirement to complete trial specific SAE reporting forms in this cohort. Cohort 2: Prospective Cohort This cohort will include: - Patients who have previously commenced maintenance Niraparib prior to the MONITOR study opening at the site and are still receiving Niraparib and in whom quality of life data is available. - Patients who are due to commence maintenance Niraparib treatment. The collection of QoL data, using EQ-5D-5L and EORTC QoL-OV28, FACT-O questionnaires will be mandatory. For patients continuing on Niraparib, data will be collected retrospectively to the point they sign the consent form, and prospectively. Going forward QoL data will not be collected for these patients unless available as part of routine clinical care and baseline QoL is available. The collection of data relating to adverse events will be mandatory. The scope of adverse events to be recorded includes AEs, SAEs, ADRs and AESIs - see section 5.3.1 for definitions of these events. Details in respect of AEs and SAEs, ADRs and AESIs will be recorded during routine clinic visits or via standard of care contact with the patient. No additional visits will be required, no study medication will be administrated, and no additional procedures will be performed outside the local routine practice as part of the trial. Patients will be managed and followed up according to routine practice. Only data available in the patient's medical record will be collected. Patients consented to cohort 2 will be asked to complete validated QoL tools; EQ-5D-5L, FACT-O and EORTC QOL-OV28. Approximately 350 patients will be enrolled with an estimated 100 in the retrospective cohort and 250 in the prospective cohort.

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.