The pharmacological effects of using cabozantinib with a light breakfast

Renal cell carcinoma (RCC) is a common cancer, with 5-year survival of 76.9%.
However, up to 30% of patients with newly diagnosed renal cell carcinoma have
metastatic disease, with a poor 5-year survival of only 14.3%. Cabozantinib is
a tyrosine kinase inhibitor (TKI) which is approved for patients with advanced
RCC (aRCC) as second-line treatment after previous VEGFR-targeting agents,
although treatment is expensive. Patients with aRCC who are treated with
cabozantinib are advised to start cabozantinib tablet formulation 60 mg daily
and take these tablets in fasted state. Interpatient variability for area under
the plasma concentration-time curve (AUC) at steady state is 38-43%. Due to
unacceptable toxicity and possibly interpatient variability in clearance, most
patients are in need of dose reduction to 40 mg or 20 mg cabozantinib during
treatment. These dose reductions do not reduce treatment costs, as all dosage
tablet formulations have the same price. Alternative dosing strategies are
warranted to improve the toxicity profile and reduce treatment costs. Taking
cabozantinib with food improves bioavailability and might reduce
gastro-intestinal toxicity. Considering the improved bioavailability and the
long half-life time of ~120 hours, a dose regimen of cabozantinib with food
might allow patients to take cabozantinib in an alternative dosing schedule
(e.g. every other day) and therefore reduce drug costs. Previous studies have
shown cabozantinib AUC increased 57% after taking cabozantinib with a high fat
meal. However, a high fat meal is not implementable in daily practice. The
percent increase in cabozantinib AUC when taken with a light breakfast is
unknown. In this study we aim to determine the increase of cabozantinib AUC
when taken with a light breakfast. Afterwards, we aim to determine if an
adjusted dose regimen of cabozantinib taken with a light breakfast leads to a
similar cabozantinib exposure compared to the standard dose regimen taken in
fasted state. In addition a patient friendly and convenient microsampling
method will be evaluated and validated for future implementation of remote
therapeutic drug monitoring and at home sampling in pharmacokinetic studies.

The primary is to investigate to the change in exposure to cabozantinib by
taking cabozantinib with a light breakfast compared to taking cabozantinib in
fasted state. The secondary objectives are to investigate the analytical
feasibility of microsampling (finger prick) for future remote cabozantinib
concentration measurements and to monitor adverse events.

A prospective, multicentre, open label cross-over phase II study.

Patients will be randomized to start with the standard regimen or the
experimental regimen. In the standard regimen, patients will take cabozantinib
in fasted condition. In the experimental regimen, patients will take
cabozantinib with a light breakfast. After at least 4 weeks on the regimen, in
order to reach steady state, pharmacokinetic samples are obtained by
venapuncture and fingerprick microsampling. When all blood samples have been
collected, the patients will switch to the other regimen. Patients will be
monitored for (S)AEs. After at least four weeks, blood samples will be
collected in exactly the same way.

Patients will be admitted to the hospital twice for one day in order to collect
eight blood samples for pharmacokinetic analyses and a single blood sample will
be collected the day after. Besides the change from taking the drug from fasted
state to fed state, no other changes in the treatment are planned and patients
will receive standard of care. A potential risk for patients participating in
this study is an increase of the exposure to cabozantinib. It is expected that
the cabozantinib AUC will increase, with a rise in AUC of 25%. This change is
not expected to affect the incidence of adverse events significantly. The risk
is therefore regarded as low.