Sorafenib pharmacokinetics in non small cell lung cancer patients: an in;vivo study using positron emission tomography

Sorafenib is used in second-line treatment of renal cell carcinoma and
hepato-cellular carcinoma. In non small cell lung carcinoma (NSCLC) patients
sorafenib is being evaluated in phase II trials. Sorafenib targets, amongst
others, VEGF and b-Raf. B-Raf is an effector in the Ras-Raf pathway. Patients
harboring a K-Ras mutation are hypothetically more sensitive to sorafenib,
because of the overstimulation of this pathway. Sorafenib is labeled with the
positron emitter 11-Carbon. Positron emission tomography (PET) studies using
[11C]sorafenib would provide a unique means to measure [11C]sorafenib
pharmacokinetics, tumor uptake and tumor response in vivo. By relating PET
measurements with tumor response, it will be possible to investigate the
potential role of [11C]sorafenib and PET as a tool for predicting sorafenib
therapy and consequently an important step in personalizing therapy.

To assess sorafenib pharmacokinetics and biodistribution, K-Ras mutational
status, tumor uptake and tumor response in NSCLC patients.

An observational study with invasive measurements.

Risk associated with participation in this study are related to 1) radiation
exposure; 2) idiosyncratic reaction to the tracer [11C]sorafenib; 3)
intravenous and arterial cannulation; 4) blood sampling; 5) discomfort during
scanning; 6) bleeding due to biopsy.

1. Radiation exposure
A PET-CT scan is a regular diagnostic imaging technique. Each study will be
conducted in compliance with the radiation safety of the department. Based on
the calculations with Olinda software that whole body radiation from
intravenous injection of 370 Mbq [15O]H2O and 370 Mbq [11C]sorafenib is
approximately 0.4 mSv and 2 mSv respectively. In addition a low dose CT scan
performed during PET scanning has a radiation dose of 1 mSV as calculated with
the *ImPACT CT patient dosimetry calculator*. Patients will undergo 2 combined
[15O]H2O/[11C]erlotinib PET-CT scans. The total amount of radiation burden is
6.8 mSv during the entire study, which is below the general accepted amount of
radiation burden of 10 mSv. To compare, every person living in the Netherlands
receives a natural background radiation dose of 2-2,5 mSv per year.

2. Idiosyncratic reaction of the tracer [11C]sorafenib
Due to the fact that only sub-pharmacological doses of [11C]sorafenib are
administered in PET studies, no [11C]sorafenib-induced side effects will be
expected in this study. A physician will be present during PET scanning.

3. Intravenous and arterial cannulation.
There is a very small risk of infection and bleeding associated with
intravenous and arterial catheters, which are prevented by proper techniques.
The venous cannulas and arterial cannulas (under local anaesthetics) will be
placed by highly qualified medical doctors of the Department of Nuclear
medicine & PET Research. However, occasionally these cannulas may cause a
haematoma.


4. Blood sampling.
Adverse events of blood sampling will be minimised by exclusion of subjects
with low haemoglobin levels (haemoglobin level must be > 6 mmol/l). No more
than 286 ml blood will be withdrawn during the two PET scans.

5. Discomfort during PET scanning.
It may be uncomfortable to lie motionless in the camera and it may cause some
subjects to feel anxious. Subjects will be made acquainted with the
surroundings beforehand. Our staff will be available to provide support, reduce
anxiety, optimise the comfort of the subject and remove the subject from the
scanner if requested.

6. Bleeding due to biopsy.
There is a small risk of bleeding during taking biopsy. To minimise these
risks, biopsies will be taken by highly qualified medical doctors of the
Department of Pulmonary Diseases.