Optimalisatie van de behandeling van uitgezaaide darmkanker met cetuximab middels opname metingen van 89Zr gelabeld cetuximab mbv PET.

3rd line standard treatment of patients with metastatic colorectal cancer (CRC) harboring K-ras wild type consists of anti-EGFR treatment with either cetuximab or panitumumab. This type of treatment has a modest but significant beneficial activity in this patient group with improved progression-free and overall survival. Although it is well known that patients with advanced CRC harboring a K-Ras mutation will not respond to anti-EGFR treatment, it is not understood why patients with K-Ras wild type CRC do not all benefit from this type of therapy. In order to optimize treatment of these patients as well as health care costs, it is extremely important to identify those patients who will respond to treatment with an EGFR inhibitor at an early stage.

We hypothesize that the differences in response to treatment with cetuximab are due to variability in the pharmacokinetics and -dynamics of the antibody. Thus, we hypothesize that patients who do not respond to anti-EGFR treatment, have insufficient drug levels in tumor tissue. We hypothesize that this is due to pharmacodynamic processes such as sequestration of cetuximab in the liver which expresses high levels of EGF receptor.

With the introduction of immuno-positron emission tomography (PET), an attractive novel option to visualize molecular interactions has been developed using the combination of PET with labeled mAbs. Cetuximab labeled with zirconium-89 (89Zr) has been successfully generated (GMP) and is available for this study. Previous studies have shown excellent stability of this compound and 89Zr is shown to be safe in humans. We will use 89Zr-cetuximab to demonstrate tumor targeting by imaging and explore the relation of uptake with treatment response. With this approach we hope to achieve a better understanding of the mechanisms of action of this therapeutic mAb in metastasized CRC and eventually develop strategies that may improve efficacy of cetuximab treatment.

N/A

The detection of 89Zr-cetuximab uptake in non-hepatic tumor lesions (present/absent; present being defined as levels measured in ROI’s > standard deviation of background +1).



Part two – Primary endpoint:

The % uptake (of total injected) 89Zr-cetuximab in non-hepatic tumor lesions as measured in ROI’s corrected for background levels.



Part two - Secondary endpoints:

1. The % uptake (of total injected) 89Zr-cetuximab in liver lesions as measured in ROI’s corrected for background levels;

2. [18F-]FDG PET measurements (SUVmax) before and after 4 weeks of treatment with cetuximab;

3. Grade of skin toxicity as measured by predefined criteria.

Patients will be treated with cetuximab. For pharmacodynamic purposes PET-imaging with 89Zr-labelled cetuximab will be performed. In addition, two [18F-]-FDG PET-CT will be performed to explore early response. Patients will undergo blood sampling and two skin biopsies for pharmacodynamic purposes of 89Zr-labelled cetuximab and kinase activity profiles, respectively.