To investigate the impact of a medication called Belzutifan on the production and subsequent metabolism of adrenaline and noradrenaline collectively termed 'catecholamines'. The study aims to identify changes in the production and metabolism of catecholamines by measuring the substance which starts the chain of catecholamine metabolism called tyrosine in patients before, during and after 5 days of taking Belzutifan 120mg daily.

This is a single centre, single arm, pilot interventional study aimed at identifying alterations in catecholamine synthesis and metabolism in 12 patients taking Belzutifan 120mg daily for five days. As this is a pilot and experimental study of a rare disease, sample size was not calculated. A study recruitment target of 12 patients was established based on the annual incidence of patients with catecholamine secreting PPGL attending our national referral centre.

There is an estimated annual incidence of 100-150 patients across all of England and an annual incidence of 15-20 patients attending Cambridge University Hospital per year.

The study protocol is 14 days. All patients will be recruited by the PI after informed consent and review of the study inclusion and exclusion criteria.

Germline genetic results performed as part of routine clinical care will be recorded for all patients. For those patients with negative germline genetic test results, tumour sequencing of available tissue or tumour tissue later removed (after the end of the study protocol) during surgery will be performed to investigate for somatic variants (genetic changes unique to the tumour cells) in specific genes which may influence how Belzutifan impacts catecholamine synthesis and metabolism.

The study protocol is 14 days including five days of intervention with Belzutifan 120mg daily for all patients. Baseline plasma tyrosine and plasma metanephrines will be performed on all patients (day 0) and at several time points after starting Belzutifan 120mg daily to examine for alterations in catecholamine metabolism. Recruited patients will attend daily for seven days and again on day 10 and day 14 and will be reviewed by the PI.

Plasma tyrosine and metanephrines will be performed using specific published research methods (liquid chromatography mass spectroscopy) and a percentage reduction in catecholamine metabolites and a percentage increase in tyrosine will be calculated for every patient at the end of the 14-day protocol.

Safety measures will include monitoring of full blood count, liver function tests and by measuring blood pressure and heart rate at baseline and at day 1-7, day 10 and day 14 in all patients recruited to the study.

Any changes in blood pressure during the study protocol will be reviewed by the PI and all changes to existing medications will be performed by the PI and recorded.

All recruited patients will be interviewed daily from day 0 to day 7 and again on day 10 and day 14 and all symptoms reported will be recorded by the PI.

Inclusion Criteria:

• Adult patients > 18 years
• Patients must have a biochemically confirmed diagnosis of a phaeochromocytoma or paraganglioma using plasma metanephrines or 24- hour urinary metanephrines and plasma or urinary metanephrines should be at least 1.5 times the upper limit of the normal reference range.
• Female patients of child-bearing potential must have a negative serum pregnancy test result within 3 days before first administration of study drug
• Able to provide informed consent

Exclusion Criteria:

• Has hypoxia, or requires intermittent supplemental oxygen, or requires chronic supplemental oxygen.
• Has clinically significant cardiac disease, including unstable angina, acute myocardial infarction, percutaneous transluminal coronary angioplasty (PTCA), or coronary artery bypass graft surgery (CABG) ≤6 months from Day 1 of study drug administration, or New York Heart Association Class III or IV congestive heart failure. Medically controlled arrhythmia stable on medication is permitted.
• Has a co-existing malignancy (in addition to PPGL)
• Has a Hb < 100g/dL
• Is on medications which may interfere with belzutifan pharmacokinetics and that cannot be stopped for the duration of the study and for 7 days after the study period (everolimus, omeprazole, esomeprazole, Fluconazole, fluoxetine, Voriconazole, Sirolimus)
• Has a known diagnosis of HIV, hepatitis B or hepatitis C