The NorCUP Trial: Improving Prognosis and Personalized Treatment in Cancer of Unknown Primary (CUP) (NorCUP)

The goal of this clinical trial is to improve diagnosis and treatment strategies for patients with Cancer of Unknown Primary (CUP) by using advanced molecular profiling to identify the likely tumor origin and guide therapy.

The main questions it aims to answer are:

Can comprehensive molecular profiling help determine the origin of CUP tumors? Does identifying the tumor origin improve treatment choices and survival outcomes compared to historical data?

Participants will:

• Undergo a new biopsy to collect tumor tissue for advanced analyses.
• Provide blood samples for circulating tumor DNA (cfDNA/ctDNA) analyses.
• Provide a fecal sample for microbiome analysis.
• Have their tumor tissue analyzed using:

Methylation profiling and comprehensive gene panel testing.

• Have the results reviewed in a specialized CUP molecular MDT meeting to determine the likely tumor origin and guide treatment.
• Have their tumor tissue samples biobanked for further exploratory whole genome sequencing (WGS) and RNA sequencing.

Study Overview

• Status: Not yet recruiting
• Conditions: Cancer of Unknown Primary Site
• Intervention / Treatment: Genetic: Comprehensive molecular profiling

• Study Type: Interventional
• Enrollment (Estimated): 350
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Eli Sihn S Steinskog, MD PhD; Phone Number: 0047; Email: eli.sihn.samdal.steinskog@helse-bergen.no

Study Locations

• Norway
  • Bergen, Norway, 5021
    • Haukeland University Hospital
    • Contact: Kjersti T Davidsen, MD PhD; Phone Number: 004755972010; Email: kjersti.tefre.davidsen@helse-bergen.no
  • Oslo, Norway
    • Oslo University Hospital
    • Contact: Elin Amdal; Email: eliaam@ous-hf.no
  • Oslo, Norway
    • Akershus University Hospital
    • Contact: Åsa D Smith; Email: Asa.Dahle.Smith@ahus.no
  • Stavanger, Norway
    • Stavanger University Hospital
    • Contact: Bjørnar Gilje; Email: bjornar.gilje@sus.no
  • Tromsø, Norway
    • University Hospital of North-Norway
    • Contact: Egil Blix; Email: egil.store.blix@unn.no
  • Trondheim, Norway
    • St Olavs hospital
    • Contact: Ola Magne Vagnildhaug; Email: ola.magne.vagnildhaug@stolav.no

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• ECOG PS 0-2.
• Life expectancy minimum 3 months.
• Radiologically verified metastatic disease (CT thorax/abdomen/pelvis) with no radiological signs of primary tumor.
• Histologically verified metastatic disease of unknown primary. Morphological and immunohistochemical findings suggesting a possible, but not definitive, origo is eligible.
• Eligible histologies include adenocarcinoma, squamous cell carcinoma, poorly and undifferentiated carcinoma and undifferentiated neoplasms.
• Clinically relevant endoscopic examinations have been performed as indicated by clinical, radiological and pathological findings, without identification of a primary tumor.
• Clinically relevant supplementary radiological examinations have been performed as indicated by clinical, radiological and pathological findings, with no radiological signs of primary tumor (e.g. PET/CT, mammography/MR mammae).
• Metastatic lesion available for biopsy. Protocol deviation may be allowed if lesion is not technically available for biopsy. For patients with metastatic lesion technically available for biopsy, the patient must be deemed medically fit to undergo a metastatic biopsy, as assessed by the investigator.
• Capable of giving signed informed consent as described in Appendix 1, which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.

Exclusion Criteria:

• Patients with any clinically significant medical or psychiatric condition which, in the opinion of the treating physician, makes it undesirable for the patient to participate in the study or which could jeopardize compliance with study requirements.
• Psychological, familial, sociological or geographical condition(s) potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial
• Patient not able to give an informed consent or comply with study regulations as deemed by study investigator.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Comprehensive molecular profiling; Tumor methylation analyses, cfDNA methylation analyses, Whole Genome Sequencing, RNA sequencing, Broad targeted NGS panel analyses	Genetic: Comprehensive molecular profiling; A fresh frozen biopsy and blood plasma for cfDNA analyses is taken upon inclusion for comprehensive molecular profiling. Results are discussed at a study specific CUP molecular MDT meeting.; Other Names: whole genome sequencing; RNA sequencing; Tumor methylation analyses; cfDNA methylation analyses; Broad targeted NGS panel

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of patients where the site of origin is identified	Site of origin identified is defined as the cases where the CUP molecular MDT concludes with a likely primary site of origin	From enrollment to the conclusion at the CUP molecular MDT at 8 weeks
Percentage of patients where treatment choice differs from empirical CUP regimen	Organ specific treatment chosen over empirical CUP treatment, based on the conclusion from the CUP MDT	From conclusion at the CUP molecular MDT to the start of subsequent treatment within a timeframe of 36 months from study inclusion

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression free survival	The length of time from the start of treatment until disease progression or death from any cause, whichever occurs first.	From the date of first administration of a treatment line to the date of progression or death, or censored if alive at time of analysis, with a timeframe of 36 months from study inclusion.
Overall survival	Length of time from CUP diagnosis until death from any cause	From date of CUP diagnosis until death from any cause or censored if alive at date of analysis, within a timeframe of 36 months from study inclusion.
Identification of tumor site using molecular profiling methods	The percentage of patients in whom the likely site of origin is identified by each molecular profiling method.	From study enrollment to the conclusion at the CUP molecular MDT at 8 weeks
Incidence of molecular alterations and use of targeted treatment in CUP patients	The frequency of molecular alterations and actionable targets in patients with CUP, and the percentage of patients receiving targeted therapy based on molecular profiling results. The impact of targeted treatment on survival will also be evaluated.	From molecular profiling to initiation of targeted therapy and follow-up for survival outcomes, within a timeframe of 36 months from study inclusion.
Impact of CUP molecular MDT assessement on previous clinical work-up	This outcome evaluates the utility of CUP molecular MDT meetings by measuring the percentage of patients for whom additional clinical work-up or pathology analyses are recommended and the concordance between local and study pathologist conclusions.	From enrollment until CUP mol MDT at 8 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Fecal Microbiome Diversity and Composition in CUP Patient	Characterization of the fecal microbiome in patients with cancer of unknown primary (CUP)	From baseline stool sample collection through completion of analyses within a timeframe of 36 months from study inclusion

Collaborators and Investigators

• Sponsor: Haukeland University Hospital

Study record dates

Study Major Dates

• Study Start (Estimated): January 1, 2026
• Primary Completion (Estimated): January 1, 2033
• Study Completion (Estimated): January 1, 2033

Study Registration Dates

• First Submitted: December 19, 2025
• First Submitted That Met QC Criteria: January 16, 2026
• First Posted (Actual): January 26, 2026

Study Record Updates

• Last Update Posted (Actual): January 26, 2026
• Last Update Submitted That Met QC Criteria: January 16, 2026
• Last Verified: December 1, 2025

More Information

Terms related to this study

• Keywords: cancer of unknown primary site; neoplasms, unknown primary
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms; Neoplastic Processes; Neoplasm Metastasis; Pathological Conditions, Signs and Symptoms; Neoplasms, Unknown Primary; Investigative Techniques; Genetic Techniques; Sequence Analysis; Sequence Analysis, DNA; Sequence Analysis, RNA; Whole Genome Sequencing
• Other Study ID Numbers: 869556

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No