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

• Comprehensive molecular profiling (Genetic), also known as whole genome sequencing, RNA sequencing, Tumor methylation analyses, cfDNA methylation analyses, Broad targeted NGS panel: 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.

Primary outcomes

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

Secondary outcomes

• Progression free survival [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.]: The length of time from the start of treatment until disease progression or death from any cause, whichever occurs first.
• Overall survival [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.]: Length of time from CUP diagnosis until death from any cause
• Identification of tumor site using molecular profiling methods [From study enrollment to the conclusion at the CUP molecular MDT at 8 weeks]: The percentage of patients in whom the likely site of origin is identified by each molecular profiling method.
• Incidence of molecular alterations and use of targeted treatment in CUP patients [From molecular profiling to initiation of targeted therapy and follow-up for survival outcomes, within a timeframe of 36 months from study inclusion.]: 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.
• Impact of CUP molecular MDT assessement on previous clinical work-up [From enrollment until CUP mol MDT at 8 weeks]: 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.

Other outcomes

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

Sex: All, ages: 18 Years to any

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.