Carcinoma of Unknown Primary (CUP): A Comparison Across Tissue and Liquid Biomarkers

Study Overview
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Brief Summary
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Patients with Carcinoma of Unknown Primary (CUP) have widespread cancer at diagnosis however the specific site of origin cannot be found, despite significant testing, making it difficult to treat. CUP has a poor prognosis; it is the 6th most common cause of cancer death in the UK. To date there have been limited studies investigating molecular genomics in CUP patients, resulting in limited evidence to evaluate whether genomic profiling has added value over and above the standard diagnostics provided in the NHS. As a result, our project will aim to; Assess genomic sequencing (both in tissue and blood) for the diagnosis and treatment guidance in CUP patients including a comparison of the effectiveness of tissue and blood based biomarkers Collect evidence to further develop technology that predicts an individual's response to a treatment Develop innovative systems of clinical data capture in patients with CUP Investigate novel biomarkers to determine the primary tumour location Approximately 120-140 CUP patients will be recruited across 7 UK NHS sites. Tumour samples will be collected from patients undergoing a standard of care procedure OR medically fit patients with accessible tumour. Archival tumour may also be obtained. Some samples will be stored for future translational research. Sequencing results alongside clinical data will be discussed by a multi-disciplinary CUP Molecular Tumour Board. They will provide oversight on the nature, clinical significance and relevance of the results. They will inform the local CUP team of any actionable genetic changes, which could potentially direct selection of a targeted therapy trial for that patient. Sequential blood samples will be collected to investigate genetic characteristics that may be able to predict response to therapy. The aggregated anonymised data will be made publicly available following completion of this trial.

Official Title
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Carcinoma of Unknown Primary (CUP): A Comparison Across Tissue and Liquid

Conditions
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Cancer of Unknown Primary Site

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Aged 16 years or over Written informed consent according to ICH/GCP and national regulations ECOG Performance status 0-2 Confirmed diagnosis of CUP as per the ESMO guidelines (described above). Patients must have; The local pathology reports confirming compatibility with CUP diagnosis and the associated slides used for the diagnosis Discussion at a local CUP MDT confirming diagnosis Accessible tumour that can be safely biopsied using radiological techniques. Biopsy may be undertaken as standard of care (surplus tissue sample to be used for this protocol), or maximum of one fresh biopsy specifically for purposes of the protocol. Subjects with inaccessible tumours for biopsy specimens but with a confirmed CUP diagnosis, may be enrolled without a biopsy upon consultation and agreement by the sponsor Availability of archival tumour sample, slides and histological report Willingness to provide blood samples on up to three occasions during the course of the study Exclusion Criteria: Patient with an immunohistochemistry profile that provides a definitive clinical indication of a primary cancer with a specific treatment Known HIV, Hepatitis B, C positive, or COVID-19 positive, due to the difficulties in handling high-risk specimens Patients who are unable to provide fully informed written consent Presence of any medical, psychological, familial or sociological condition that, in the investigator's opinion, will hamper compliance with the study protocol and follow-up schedule Bleeding diathesis (patients' on anticoagulation are permitted to enter the trial if anticoagulation can be safely managed to enable fresh tumour biopsies and blood sampling) Conditions in which research biopsies or blood sampling may increase risk of complications for the patients and/or investigator

Ages Eligible for Study
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Minimum Age: 16 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To sequence tumour tissue and circulating tumour DNA from approximately 120- 140 patients with CUP in order to evaluate the activation state of various oncogenic pathways and improve treatment stratification approaches |  | 18 months | 
| To establish a genomic reporting mechanism whereby clinically relevant and potentially 'actionable' abnormalities found during sequencing/molecular characterisation can be reported to patients |  | 18 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To obtain archival tumour specimens, fresh tissue and sequential blood samples from approximately 120 - 140 patients with CUP |  | 18 months | 
| The comparative assessment of alternative assay methods (such as ctDNA) in parallel with whole genome sequencing in the diagnosis and treatment stratification for patients with CUP |  | 18 months | 
| To collect samples for future analysis for additional molecular characterisation techniques for detection of actionable aberrations. Examples include RNA sequencing, IHC, proteomics, methylation, analysis of immuno-biomarkers |  | 18 months | 
| To perform whole genome sequencing in patients where enough tumour tissue is available to explore novel predictive and resistance biomarkers |  | 18 months | 
| To build on close collaborations between the NHS CUP Hospitals, and external collaborators to progress basic/translational research models to investigate biomarkers to treatment in CUP and key biological drivers of this disease. |  | 18 months | 
| Collect evidence investigating the most effective way to stratify patients with CUP onto treatment. |  | 18 months | 
| To understand whether liquid biomarkers in CUP can be used to stratify patients and give prognostic information |  | 18 months | 
| Develop a data collection repository within the NHS for patients with CUP |  | 18 months |