Treatment optimization of cetuximab in patients with metastatic colorectal cancer based on tumour uptake of 89Zr-labeled cetuximab assessed by PET

3rd line standard treatment of patients with metastatic colorectal cancer (CRC)
harbouring 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
harbouring 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 tumour 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 labelled mAbs. Cetuximab labelled 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 tumour 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.

The main objective of the first part of the study is the demonstration of
89Zr-cetuximab uptake in non-hepatic tumour lesions.
The main objective of the second part is the association between 89Zr-cetuximab
uptake in non-hepatic tumour lesions and treatment outcome.


Secondary objectives:
1) To investigate whether there is an association between levels of uptake of
89Zr-cetuximab in the liver compared to levels of uptake in non-hepatic tumour
lesions.
2) To explore whether the response observed on [18F]-FDG-PET can serve as an
early response marker for future response to targeted therapy according to
RECIST 1.1.
3) To explore whether there is an association between 89Zr-cetuximab uptake in
non-hepatic tumour lesions, grade of skin toxicity and response according to
RECIST 1.1.

Single centre, two step non-randomized intervention study

Patients will be treated according to standard care 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.

Upon enrolment in this study, patients will be asked to undergo two skin
biopsies during treatment. During therapy, follow-up will include standard
laboratory analysis, immuno-PET-CT and [18F-]-FDG PET-CT on regular visits to
the outpatient clinic. Side effects of the medication and adverse events as a
consequence of the skin biopsies may occur. The radiation exposure is
acceptable and requires no shielding after injection of 89Zr-labelled
cetuximab. Patients may benefit from disease regression or stabilization as
cetuximab has proven clinical benefit in this patient population.