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| CUP Trials | |
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| Name | CUP Trials |
CUP Trials are a series of clinical investigations focused on cancers of unknown primary, designed to evaluate diagnostic strategies, therapeutic regimens, and translational biomarkers across multidisciplinary settings. They were developed to integrate oncologic, pathologic, radiologic, and molecular approaches to improve survival and quality-of-life outcomes in patients presenting with metastatic disease without an identified primary site. The designs draw on precedents from oncologic trials, precision-medicine consortia, and international cooperative groups.
The CUP Trials aim to reconcile disparate practices in the management of cancers of unknown primary by combining methods from randomized controlled trials, prospective cohort studies, and basket-trial frameworks. They connect institutions such as National Cancer Institute, European Organisation for Research and Treatment of Cancer, American Society of Clinical Oncology, World Health Organization, and national cancer centers to create harmonized protocols. Key collaborators include academic medical centers like Memorial Sloan Kettering Cancer Center, MD Anderson Cancer Center, and Gustave Roussy, as well as networks such as European Reference Networks, UK National Health Service, and consortia like The Cancer Genome Atlas and International Agency for Research on Cancer.
Cancers of unknown primary present clinical dilemmas exemplified by case series and registries from institutions including Mayo Clinic, Johns Hopkins Hospital, Royal Marsden Hospital, and national databases such as SEER Program. Historical trials and guideline statements from bodies like National Comprehensive Cancer Network and European Society for Medical Oncology influenced protocol development. Molecular profiling initiatives from Foundation Medicine, Illumina, and projects like METABRIC provided rationale for using genomic classifiers. Epidemiologic studies from Centers for Disease Control and Prevention, Cancer Research UK, and cohort analyses in publications from Lancet Oncology and Journal of Clinical Oncology highlighted unmet needs in diagnostic yield and survival, motivating integrated trials that incorporate imaging from PET-CT centers, pathology workflows from College of American Pathologists, and biomarker validation aligned with Clinical Laboratory Improvement Amendments standards.
The CUP Trials employed adaptive designs inspired by platform trials such as RECOVERY Trial, master protocols like NCI-MATCH, and Bayesian frameworks used in I-SPY 2. Randomization schemes drew on methods established in trials like KEYNOTE-024 and CheckMate 057, while stratification factors mirrored those from studies such as FOLFIRINOX trials and hormone-receptor studies exemplified by ATAC Trial. Endpoints and interim analyses adopted conventions from regulatory submissions to Food and Drug Administration and European Medicines Agency. Multicenter coordination used data standards from Clinical Data Interchange Standards Consortium and trial management approaches from Duke Clinical Research Institute.
Eligibility criteria reflected consensus statements from organizations including Royal College of Pathologists, Society for Immunotherapy of Cancer, and specialty guidelines from ASCO. Inclusion required histologic confirmation assessed by laboratories accredited by College of American Pathologists and diagnostic imaging per protocols from European Society of Radiology and American College of Radiology. Biomarker-driven arms required molecular profiling provided by vendors such as Foundation Medicine or academic platforms like Broad Institute sequencing cores associated with The Cancer Genome Atlas. Exclusion criteria paralleled safety considerations from trials at Dana-Farber Cancer Institute and geriatric assessments influenced by work at Mayo Clinic. Enrollment targets were informed by population incidence data from SEER Program and trial feasibility analyses used by ClinicalTrials.gov registries.
Therapeutic regimens encompassed site-specific treatments when a putative primary was suggested, drawing on chemotherapy protocols from studies such as FOLFIRI, FOLFOX, and targeted-therapy experience from HER2-targeted therapy trials like TOGA Trial. Immune-oncology arms referenced evidence from KEYNOTE-189 and CheckMate-227, while precision-medicine arms matched patients to agents validated in projects like NCI-MATCH and TARGET trial. Radiotherapy protocols adhered to standards from American Society for Radiation Oncology, and surgical considerations were guided by practices at centers like Memorial Sloan Kettering Cancer Center and Royal Marsden Hospital. Supportive-care approaches referenced guidelines from European Society for Medical Oncology and palliative frameworks from World Health Organization.
Primary endpoints included overall survival and progression-free survival consistent with metrics used in Journal of Clinical Oncology publications and regulatory submissions to Food and Drug Administration. Secondary endpoints encompassed objective response rates defined by RECIST criteria, quality-of-life measures using instruments from EORTC, and health-economic outcomes informed by analyses published by National Institute for Health and Care Excellence. Biomarker endpoints evaluated concordance with molecular classifiers from Foundation Medicine, expression signatures reported by The Cancer Genome Atlas, and predictive markers studied in IMPACT Trial-like analyses. Safety endpoints followed toxicity grading in Common Terminology Criteria for Adverse Events.
Statistical plans employed methodologies from biostatistical centers such as Fred Hutchinson Cancer Research Center and analytic techniques drawn from literature in Biometrika and Statistics in Medicine. Interim monitoring used data safety oversight models from Data Safety Monitoring Board best practices and group-sequential methods seen in trials like PLATO Trial. Data management conformed to standards from Clinical Data Interchange Standards Consortium and privacy frameworks aligned with Health Insurance Portability and Accountability Act and General Data Protection Regulation where applicable. Central laboratories and bioinformatics analyses coordinated with platforms developed at Broad Institute and European Bioinformatics Institute.
Ethical oversight referenced declarations such as Declaration of Helsinki and regulatory pathways through agencies including Food and Drug Administration, European Medicines Agency, and national ethics committees like Institutional Review Board panels at participating centers. Informed consent procedures reflected templates from World Health Organization ethics guidance and data-sharing policies were aligned with principles endorsed by Global Alliance for Genomics and Health and repositories like dbGaP where controlled-access genomic data were deposited. Collaborative agreements involved contracting models used by European Organisation for Research and Treatment of Cancer and intellectual-property considerations mirrored experiences from public–private partnerships involving Foundation Medicine and academic institutions.
Category:Clinical trials