An Experimental Study of Belzutifan Impact on Catecholamine Metabolism

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.