Trial Information

Cytochrom p450 3A4 and 1A2 Phenotyping for the Individualization of Treatment With Sunitinib or Erlotinib in Cancer Patients

Objectives:

The primary objective of this study is to show that the individual CYP3A4 and
CYP1A2-phenotype as assessed by probe drugs predicts drug exposure to sunitinib and
erlotinib. Secondary objectives of the study are to define the correlation between the
individual CYP-phenotype and treatment-related toxicity, testing the feasibility of drug
bioanalysis from patient's dry blood spots (DBS), build an integrated covariate model on
sunitinib and erlotinib pharmacokinetics and define a dosing algorithm for both sunitinib
and erlotinib based on the individual CYP-phenotype.

Study endpoints:

Primary endpoint:

• To show that individual drug clearance of sunitinib or erlotinib is significantly higher
in patients with a high-activity CYP3A4/1A2-phenotype.

Secondary endpoints:

- To specify the correlation between the CYP-phenotype and treatment-related toxicity.

- To assess the feasibility of drug bioanalysis from patient's dry blood spots (DBS).

- To build an integrated covariate model of sunitinib and erlotinib pharmacokinetics to
define the quantitative relationship between the CYP-phenotype activity and drug
exposure.

- To define a dosing algorithm for both sunitinib and erlotinib based on the individual
CYP-phenotype using data simulations on the previously defined population covariate
model.

Trial Design:

Prospective, nonrandomized, pharmacological cohort study.

Main selection criteria

- Histologically or cytologically confirmed renal-cell cancer (sunitinib),
gastrointestinal stromal tumor (sunitinib) or non small-cell lung cancer (erlotinib)

- Both early or advanced tumor stage

- Indication for the therapeutic use of either sunitinib or erlotinib

- Written informed consent and willing to undergo PK-sampling

- Adequate organ function

- No concurrent radiotherapy or systemic anticancer treatment with another drug

Trial Duration The present study is projected to start in June 2011, with the inclusion of a
total of 60 patients (at least 25 patients for each sunitinib and erlotinib). The study is
expected to finalize patient accrual in December 2013.

Statistical considerations The trial is designed to show a linear inverse relationship
between the individual CYP-phenotype and total drug steady-state AUC (sunitinib plus SU12662
and erlotinib plus OSI-420, respectively), whereat CYP1A2 only accounts for the metabolism
of erlotinib. With the inclusion of 60 patients, the study has a power of 90% to detect a
relevant relationship between the CYP-phenotype activity and sunitinib/erlotinib
steady-state AUC, with a regression coefficient of >0.4 for the H1-hypothesis (and accepting
a regression coefficient of >0.1 for the H0-hypothesis) at the 5% significance level.

Trial Treatment Sunitinib: 50 mg p.o. daily for 4 out of 6 weeks, or 37.5 mg daily
continuous until disease progression, unacceptable toxicity or withdrawal of informed
consent.

Erlotinib: 150 mg p.o. daily until disease progression, unacceptable toxicity or withdrawal
of informed consent.

Potential study outcome This study makes a significant contribution to global efforts for
more individualized anticancer treatment. If successful, we will be able to make dosing
recommendations for sunitinib and erlotinib based on a simple probe drug assay.