Imaging of [11C]erlotinib pharmacokinetics in non small cell lung cancer patients; an in vivo study with positron emission tomography

Over the last decade PET/CT has emerged as an important tool for staging,
diagnosis, early response measurement and tumour surveillance during follow-up.
In routine clinical studies use is made of [18]FDG, an analogue of glucose,
which allows for imaging glucose metabolism. Although enhanced glucose
metabolism is seen in most tumours, abnormal metabolism is not specific for
malignancies and there is a continuing search for other, more tumour specific,
tracers. One example is erlotinib, a small molecule which belongs to a group of
cancer drugs known as epidermal growth factor receptor (EGFR) inhibitors by
inhibition of the enzyme tyrosine kinase. Erlotinib is under investigation as a
possible treatment for many tumor types, including pancreatic cancer, ovarian
cancer and head and neck cancer. Clinical trials were performed with
monotherapy or combination therapy with erlotinib in NSCLC. However, often the
efficacy of these agents is limited due to T790M mutation in the EGFR coding
gene. This mutation is thought to cause resistance by sterically blocking
binding of tyrosine kinase inhibitors, such as erlotinib. From phase III
clinical studies it has been concluded that addition of EGR-TKI*s, such as
erlotinib and gefitinib, to standard chemotherapy, does not improve survival
(Giaccone et al., Herbst et al. 2004, Herbst et al., 2005). As it was
discovered that genetic mutations are associated with sensitivity to erlotinib,
it is interesting to study the relationship between EGFR mutations and clinical
response in patients with NSCLC (Lynch et al., Pao et al.). Furthermore, EGFR
expression may be important for both tumour growth and survival. In some
reports, EGFR overexpression has been correlated with chemoresistance and poor
prognosis (Selvaggi et al., Buchholz et al, Wang et al). Taken together, it
will be very interesting to have knowledge about tumoral EGFR density and
mutations. Positron emission tomography (PET) may be a useful technique to
visualize and quantitate these items. This study will give insight in the
relationship between EGFR mutation status and density, [11C]erlotinib
pharmacokinetics and tumor accumulation, and tumor response. This study will
therefore provide clues to come to optimized personalized targeted therapy.

Primary Objective:

To study the tumour pharmacokinetics of [11C]erlotinib in NSCLC patients in
vivo and relating uptake with EGFR mutations, obtained from tumour biopsies.

Secondary Objective(s):
1. to define the test-retest reproducibility of [11C]erlotinib PET measurements
in lung cancer patients.
2. to validate the use of venous instead of arterial blood samples for
metabolite analysis and measurement of plasma radioactivity concentrations.
3. to develop a tracer kinetic model for quantitative analysis of
[11C]erlotinib PET studies.
4. to study the relation between tumor blood flow and [11C]erlotinib uptake in
tumors

This is an observational feasibility study with invasive measurements.

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

1. Radiation exposure
The total amount of radiation burden will be 6.8 mSv during the entire study.

2). Idiosyncratic reaction of the tracer [11C]erlotinib
No [11C]erlotinib-induced side effects will be expected in this study.

3). Intravenous canulation.
There is a very small risk of infection and bleeding or haematoma.

4). Blood sampling.
No more than 250 ml blood will be withdrawn.

5). Discomfort during PET scanning.
It may be uncomfortable to lie motionless in the camers and it may cause some
subjects to feel anxious.

6) Bleeding due to biopsy.
There is a small risk of bleeding during taking tumor biopsy.