An Open-label Single-arm Pharmacokinetic Trial, Investigating the Effect of CYP3A4 inhibitor Ritonavir on the Pharmacokinetics of Erlotinib

The standard therapy for non-small cell lung cancer (NSCLC) has been
chemotherapy for decades. By identification of oncogenic driver mutations in
NSCLC, the treatment of this malignancy has been improved. The most common
oncogenic drivers are epidermal growth factor receptor (EGFR), anaplastic
lymphoma kinase (ALK), ret proto-oncogene (RET) and receptor tyrosine kinase 1
(ROS1). These oncogenic drivers can be successfully treated by tyrosine kinase
inhibitors (TKI). By identifying more (potential) driver genes, the increase
in available TKI*s and the possibility for multiple treatment lines, the amount
of TKI use will keep rising in the coming years. Since the cost of this
treatments will cover a large part of healthcare budget, new treatment
strategies are needed to use TKI*s as effectively as possible. Currently, the
knowledge about alternative treatment schemas is limited.

Erlotinib is a tyrosine kinase inhibitor(TKI), which inhibits the (activated
mutated) epidermal growth factor receptor (EGFR). Erlotinib has several
indications in e.g. non-small cell lung cancer (NSCLC) as maintenance therapy
and in pancreatic cancer. In other tumortypes such as colorectal cancer and
biliary cancer, EGFR overexpression may occur as well, indicating that
erlotinib treatment in these cancers could be potentially therapeutic. There is
a link between erlotinib exposure and toxicity. The link between the amount of
exposure to erlotinib and response is not yet established.

Erlotinib is predominantly (~70%) metabolized by cytochrome P450 3A4 (CYP3A4),
with CYP1A2 being responsible for the other *30%. Co-administration of the
potent CYP-3A4 inhibitor ketoconazole increased the erlotinib exposure (AUC)
and maximum concentration (Cmax) approximately by two-fold (mean ratio from
0.88 to 1.64, and 0.83 to 1.67, respectively), in healthy non-smoker males.
Ciprofloxacin, an inhibitor of CYP3A4 and CYP1A2, co-administration resulted in
an erlotinib AUC and Cmax increase of 39% and 17%, respectively.

Based on the above, the aim of this study is to investigate whether it is
possible to decrease the dose of erlotinib when it is co-administrated with
CYP3A4 inhibitor ritonavir. Also, this study will provide data about the
pharmacokinetics of erlotinib with a highly potent CYP3A4 inhibitor ritonavir,
which can be used as future guidance on dosing instructions and adverse events
expectations when in daily care erlotinib is given to patients using a highly
potent CYP3A4 inhibitor.

Primary:
1. Effect of the highly potent CYP3A4 inhibitor ritonavir on the
pharmacokinetics (PK) of erlotinib, measured as AUC0-24h, AUCmean, Cmax and
Cmin

Secondary objective
1. Safety of the CYP3A4 moderator ritonavir in combination with erlotinib,
which will be measured as the incidence and severity of adverse events with and
without ritonavir, according to CTC-AE v4.03.
2. The correlation between the pharmacokinetics, measured as AUC0-24h, AUCmean,
Cmax and Cmin of ritonavir and toxicity according to CTC-AE v4.03
3. Study the effect of the highly potent CYP3A4 inhibitor ritonavir on the
pharmacokinetics (PK) of the active metabolite of erlotinib, OSI-420 , measured
as AUC0-24h, AUCmean, Cmax and Cmin.
4. Quantification of ctDNA, determined with Droplet digital PCR (ddPCR)

This is a single-arm, open-label, pharmacokinetic trial. A schematic overview
of the study is presented in figure 1. An overview of the study schedule is
shown in Table 1. We will exam the effect of a highly potent CYP3A4 inhibitor
ritonavir on the PK of erlotinib and thereby determine if it is possible to
halve the dose of erlotinib by co-administration of CYP3A4 inhibitor ritonavir.
All included patients are treated with single agent erlotinib 150mg QD for at
least 4 weeks. At day 1 a PK measurement will take place (at steady state
erlotinib 150mg QD). Since the half- life of erlotinib is 36 hours, steady
state is reached with 5x36 = ~180 hours (7.5 days). Patients will start with
erlotinib 75m QD at day 2 till day 8 of the study. From day 9 till day 15,
patients will be treated with erlotinib 75mg QD + ritonavir 200mg QD. At day
15, a second PK measurement will take place. After day 15 patients will
continue treatment of single agent erlotinib 150mg QD. Since there is no value
of -and the potential risk of two CT-scans in one week, we do not perform
response evaluation by CT-scan. Therefore, will monitor the mutation status in
plasma ctDNA during treatment as surrogate response measurement.

All subjects will receive erlotinib 75mg for 14 days. From 7 days, this will be
combination with ritonavir for CYP3A4 inhibition.

There is a risk of additional toxicity, as we expect an increase in erlotinib
exposure if taken combined with ritonavir. However, this risk is minimized by
the short duration of the intervention (only seven days) and we halve the dose
of erlotinib when it is combined with ritonavir.
Ritonavir has been administered to healthy volunteers up to oral doses of 600
mg at 12-hour intervals. Vomiting, nausea, and abdominal pain occurred
frequently especially during the first few weeks of therapy, but only at the
highest doses. These side-effects correlated with ritonavir plasma levels5.
Since ritonavir in our study is administered at much lower doses and not as
frequently as in the study reported in the literature performed in healthy
volunteers, no serious side effects are expected from ritonavir in this study.
By halving the dosage, patients are temporary exposed to a lower dose of
erlotinib. We do not expect this will be a problem, given the large therapeutic
index of erlotinib.
Safety assessments, including measurement of vital signs, WHO performance
status, hematology and clinical chemistry tests and toxicity assessments will
be performed.
In our opinion, the remaining risks are acceptable for the subjects
participating in the study.