Investigating the occurrence of everolimus long-term side effects by follow up of everolimus trough blood concentrations.

Metastatic (Hormone-Receptor [HR]-positive, HER2-negative) breast cancer (BC),
advanced or unresectable neuroendocrine tumours of pancreatic (pNET),
gastrointestinal or lung origin and metastatic renal cell carcinoma (mRCC) are
diseases with poor outcome. Everolimus is part of palliative treatment and
increases patients* median progression-free survival (PFS) with 4.6 months in
metastatic BC (mBC), 7 months in (p)NET and 3 months in mRCC. However, serious
adverse events (AEs) occur frequently; stomatitis up to 67%, pneumonitis up to
15%. This reduces effectiveness of everolimus, because AEs are managed with
dose reductions, treatment interruptions or even complete discontinuation of
everolimus.

Therapeutic-drug-monitoring (TDM) (i.e. measurement of everolimus whole
blood levels after venipuncture) is used to adjust the prescribed daily dose,
to maintain effective everolimus whole blood concentrations, with the lowest
possible risk of AEs. In addition, TDM is a useful tool for early detection of
non-adherence, and might also be used to monitor the effects of drug-drug
interactions and food effects.While TDM has been common in transplantation
medicine for 10 years, it has not been implemented in oncology. The importance
of TDM in oncology is, however, supported by previous research which showed
that a 2-fold increased everolimus whole blood trough concentration (Cmin) was
associated with a short-term risk of grade >= 3 pulmonary events (relative risk
[RR] 1.9; 95% CI 1.1-3.3], stomatitis events (RR 1.5; 95% CI 1.1-2.1) and
metabolic events (RR 1.3 95% 1.0-1.7). Moreover, an exposure-toxicity
relationship of everolimus in patients with thyroid cancer was observed, since
initial everolimus concentrations could be associated with early toxicity (< 12
weeks), i.e. stomatitis. However, the association between initial everolimus
measurements) and long-term AEs (>=12 weeks, e.g. pneumonitis, anorexia and
anemia) of any grade and the need for everolimus dose reductions could not be
made. Since levels ±>18 µg/L were associated with toxicity, we assume that the
upper therapeutic window of everolimus in the oncologic setting will be ±18 µg/
L. Therefore, an upper threshold of >18 µg/L was considered for this study.
Similarly, a tendency to improved PFS and overall survival (OS) was observed
when Cmin in steady state (CminSS) was above 14.1 µg/L. This seems to be the
lower limit of the therapeutic window.

However, the following knowledge gaps exist: 1. It is unknown whether
everolimus whole blood trough levels (over time) predict long-term AEs (e.g.
pneumonitis, anorexia and anemia). 2. The optimal concentration range for
everolimus, with the treatment of mBC, mRCC, or (p)NET is unknown, especially
the upper limit associated with toxicity. 3. It is unknown what everolimus
concentration level is associated with the need for everolimus dose reductions.

Primary Objective:
To investigate the association between the everolimus trough levels over time
and the onset of National Cancer Institute Common Terminology Criteria for
Adverse Events (NCI-CTCAE) v4.0 grade 2, 3 or 4 late AEs (i.e. from treatment
period >=12 weeks onward).

Secondary Objective:
- To investigate the association between the everolimus trough levels over time
and the onset of NCI-CTCAE v4.0 grade 2, 3 or 4 early AEs (i.e. from
treatment period < 12 weeks).
- To establish the association of trough concentrations of everolimus obtained
via venipuncture and trough concentrations obtained via finger prick in the
oncology population.
- To assess the feasibility of the novel finger prick DBS method in the
oncology setting.
- To investigate the association between everolimus trough levels (over time)
and the need for everolimus dose reductions.

Observational cohort study

The research is low-risk as there are minimal invasive procedures. Subjects can
experience pain, irritation and redness of the skin after the collection of
blood via the venous blood method and the finger prick method (NB. the finger
prick method will only be performed for patients treated in the MUMC+ or
Radboudumc hospital). Furthermore, patients need to keep up with their diary.
The use of everolimus is associated with adverse effects, however, these
adverse effects are not related to this study.
There will be no direct benefit to the participants.
The importance of the study is to investigate the association between the
bloodconcentration and the long term adverse effects of everolimus.