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To keep up with all studies is particularly difficult given the extreme heterogeneity (clinical, pathologic, cancer types) of the CUP syndrome and the lack of consistency of thinking by CUP experts and investigators. In recent years and even months there are three main clinical themes at play:
• The first is diagnosis of the cancer type in CUP (not the anatomical primary site) is critical to optimal therapy for each patient and should be site-specific therapy similar to the approach used world- wide for patients with known advanced cancer types in which the anatomic primary site is known. Many oncologists/hospitals etc. do not use all the tools we now have to determine the cancer type, but if done the specific cancer type could be determined in 90-95% of all CUP patients.
• The second theme is the use of next generation sequencing (comprehensive molecular profiling) of a biopsy specimen looking for actionable genetic alterations which may be targeted with appropriate drugs. Comprehensive molecular profiling cannot determine the specific cancer type except for rare exceptions.
• The third theme is immunotherapy mainly now with immune checkpoint blockers and this is related closely to the second theme since we have now have several markers in cancer cells which can predict a favorable response to these checkpoint blockers.
• Studies with empiric chemotherapy as one size fits all are disappearing and rightfully.
Most of the “important” ongoing studies shown below are based on one or more of these themes. The trials shown below are those that the CUP Foundation knows about, but there will be others. We are always pleased to receive new or updated information.
This is an international Phase II trial taking place now in 33 countries. Now closed – findings expected Autumn 2023. All patients screened on or prior to 31 Oct 2022 will continue in the study as usual.
There are 10 centres in the UK . The aim is to recruit around 790 patients worldwide with 76 people from the UK. More comprehensive details of the trial for clinicians and interested patients – including worldwide centres – are shown here on clinical trials.gov
[updated Mar 23]
This is an international Phase II trial taking place in 33 countries. Details of the trial – the trial design – are shown in a patient-friendly format on the CRUK website here. There are 10 centres in the UK:
Now closed. 120 patients recruited. (Mar 2023). This is a trial, led by the Christie, examining genetic changes in CUP tumours alongside blood-based biomarkers, which can help reveal the origins of a person’s cancer and predict responses to existing or new treatments. More details
Royal United Hospitals Bath NHS Foundation Trust
Velindre Cancer Centre, Cardiff,
Edinburgh Cancer Centre
UCL Cancer Institute, London,
The Christie NHS Foundation Trust, Manchester,
Northern Centre for Cancer care, Newcastle,
Torbay Hospital, Torquay,
This is a Phase II, Two‐Stage, Trial of Pembrolizumab in Cancer of Unknown Primary.
Doctors normally treat CUP with chemotherapy but this trial uses an immunotherapy drug instead. Pembrolizumab, can help the immune system to detect and fight cancer cells.
The immune system is the body’s natural defence system and it sends certain types of cells, called T cells, throughout the body to detect and fight infections and diseases—including cancer. However, cancer cells may use the PD-1 (programmed death receptor -1) pathway to hide from T cells and this stops T cells from attacking cancer cells thus allowing the cancer to grow and spread. Pembrolizumab works by blocking the PD‐1 pathway.
The aim of this study is to:
CUPem has two cohorts:
The intention is to recruit 77 patients (20 patients to Cohort 1 and 57 patients to Cohort 2. As at mid Nov 2020, the trial is close to reaching the maximum number for Cohort 1 patients but is open for Cohort 2.
The treatment period is made up of 3‐week cycles. During each cycle, the patient will receive 200mg of Pembrolizumab by intravenous infusion every 3 weeks.
The trial hospitals are:
You do not have to live in London to be accepted onto the trial but you will need to be able to travel to London for treatment.
Contact. For further information contact the Senior Clinical Research Practitioner at Hammersmith Hospital: [email protected]
Imperial Clinical Trials Unit – Department of Surgery and Cancer, Imperial College, Hammersmith Hospital, Du Cane Road, London W12 0NN
This study aims to look at CUP tumours in more detail to understand better the spread of the cancer and potentially find the tumour origins. Participants would be asked to agree to have samples of their tumours taken after death as well as blood to supplement samples taken during diagnosis and treatment. Even from only a small number of participants studies such as this enable a wealth of unique, detailed information about a tumour including genetic changes, tumour environment and immune interactions and may reveal why the tumours origins have remained unknown. Results from this study will not directly benefit the participants but will contribute to greater understanding of CUP tumours for future patients.
Further information can be obtained by emailing the-[email protected]
funded by NCRI/CRUK and co-ordinated by the CRUK Clinical Trials Unit in Glasgow. There are more details here. The study is in two parts: the aim of the first (translational) part is to prospectively validate new tools in diagnosis (including molecular profiling, metabonomics of blood and urine for response and toxicity prediction and a proposed immunohistochemistry classifier). The hope is that, in the future, scientists can find a diagnostic indicator of the primary site simply, rather than trying a whole barrage of investigations. Patients in whom a primary site is not identified can then be entered into the second (clinical) part of the trial. This part aims to establish the efficacy of the ECX chemo regimen (ECX stands for the drugs: Epirubicin, Cisplatin and Capecitabine) with and without Vandetanib (an inhibitor of different intracellular signaling pathways involved in tumour growth, progression, and angiogenesis). The treatment will last initially for 3 months and there will be subsequent monitoring. Patients can withdraw from the trial at any time without giving a reason. The trial may help in the future with selecting the best chemotherapy for patients with CUP. Overall, this study should allow a more logical framework to be derived, both clinically and biologically, as to how highly metastatic cancers may be efficiently and economically investigated and managed in the future. It will be some years before the findings are available from this trial.
For general information about trials in the UK see http://www.cancerhelp.org.uk/trials/finding/how-do-you-find-a-trial
CUP biology. Study in Greece on CUP biology as part of a multinational TCGA study. 25 patients with CUP managed at cancer centers affiliated with HeCOG (Hellenic Cooperative Oncology Group), whose formalin-fixed paraffin-embedded (FFPE) tumour blocks and clinicopathological data are stored in the Department of Medical Oncology, University of Ioannina. FFPE biopsies from another 25 patients with metastatic solid tumours (lung, breast, colorectal, pancreatic, cholangiocarcinoma) will be studied as a control population.
GEFCAPI 04 (a la carte) NOW CLOSED
ThisPhase III trial began in 2010 under the auspices of the Groupe d’Etude des Carcinomes de Primitifs Inconnus (GEFCAPI) with the co-operation of investigators from the Netherlands, Denmark, and Sweden.. The study is a phase III randomized trial with the aim of demonstrating the superiority of a molecular analysis-oriented treatment versus empiric chemotherapy in patients with CUP. After accrual, patients will be randomized to receive: either the Cisplatin-Gemcitabine regimen (arm A) – or a treatment considered as standard at the time of patient inclusion based on the primary cancer suspected by the Pathwork Tissue Of Origin® Test, which may consist in a chemotherapy regimen and/or a so-called targeted therapy (arm B).
The majority of CUP trials take place in the USA and those shown below are illustrative. There are 2 large studies in the United States accruing patients with any type of advanced cancer including CUP which are match trials requiring comprehensive molecular profiling of a biopsy and matching potentially actionable genetic alterations with a number of targeted drugs. These trials are ongoing. The 1st is sponsored by the National Cancer Institute (MATCH TRIAL) and the 2nd by the American Society of Clinical Oncology(ASCO)-the Targeting Agent and Profiling Utilization Registry (TAPUR TRIAL).
At the Sarah Cannon Research Institute
• In progress. A large retrospective review of greater than 1000 CUP patients all having had a molecular cancer classifier assay (usually the 92-gene RT-PCR assay CancerTYPE ID) performed on their biopsies since 2008. Sarah Cannon are evaluating the specific cancer types diagnosed (more than 30) and looking at their clinical features, pathology including IHC and their therapies/outcomes.
• In planning for 2018 – a study evaluating immunotherapy with a combination of immune checkpoint blockers (CTLA-4 and PD-1 inhibitors) in CUP patients. This will initially evaluate 40 patients in approximately 15 sites. Molecular testing to determine the cancer type as well as comprehensive molecular profiling and PD-L1 evaluation of the biopsy specimens will be accomplished. Tumor mutation burden (TMD) and other molecular markers associated with improved response to immune checkpoint blockers will be assessed and response, PFS and overall survival will be correlated with the cancer type and molecular findings.
SUPER – Solving Unknown Primary cancER.
Sponsor: Peter MacCallum Cancer Centre, Melbourne, Australia.
This is a prospective cohort study to create a national information resource and improve the understanding of the molecular biology, clinical, quality of life and psychosocial characteristics of patients with Cancer of Unknown Primary (CUP). The information resource is a national cohort of CUP patients with associated biospecimens, clinical, quality of life, health economic and psychosocial data. The study is currently active and will recruit 300 patients from eleven metropolitan and regional sites across Australia. The study is recruiting participants in Victoria, New South Wales, South Australia, the Northern Territory and the Australian Capital Territory. As part of the SUPER team’s larger body of work, current research accessing the samples collected as part of this study will look to determine the frequency of clinically actionable mutations in CUP tumour samples and evaluate the impact of performing molecular diagnostic tests and feedback of results to influence clinical care of CUP patients.
The SUPERDx is a site-of-origin test newly developed by the SUPER team at the Peter MacCallum Cancer Centre. Using existing data from our own, and other studies, we have derived a gene signature that is used to predict the site-of-origin of an unknown tumour sample. We currently use this test, alongside next generation sequencing mutation profiling, to potentially direct more tailored treatment. The clinical utility of these results is being measured by the impact of this information on clinical decision-making and patient outcomes. The project also seeks to establish reliable estimates for quality of life and psychosocial needs across the CUP illness trajectory and to identify similarities and differences between CUP and advanced cancer patients with a known primary from baseline to 12-month follow-up. The long-term objectives of this project are to: significantly improve the diagnostic assessment of CUP patients, integrate new treatment approaches based on molecular therapeutics and likely site of origin, and develop tailored supportive care intervention programs for patients with CUP.
Fudan University. Phase III study (2017-2020) designed to evaluate the value of tissue-of-origin (ORIGIN-PanCA○R) profiling in predicting primary site and directing therapy in patients with cancer of unknown primary.