Optimalisatie van de behandeling met cetuximab voor patienten met uitgezaaide dikkedarm kanker door de opname van 89-zirconium gelabeld cetuximab te beoordelen middels PET-scan

Currently, third line systemic treatment for patients with advanced, wild type K-RAS and as has recently been demonstrated with wild type N-RAS (thereafter referred to as wild type RAS) colorectal cancer (CRC) includes EGFR inhibition with the anti-EGFR antibody cetuximab. 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 known that patients with advanced wild type RAS CRC will not respond to anti-EGFR treatment, it is not understood why patients with wild type RAS CRC do not all benefit from this type of therapy. Apart from other potential gene mutations involved in response to treatment, differences in the variability of pharmacokinetics may play a crucial role in the response to anti-EGFR treatment. In non-responders insufficient drug accumulation may occur in the tumor due to pharmacokinetic processes, such as cetuximab sequestration in the liver which expresses high levels of EGFR, or due to low levels of EGFR expression in tumor lesions. Our main hypothesis is that uptake of cetuximab in metastases is required for response and that achieving cetuximab uptake by increasing its dose will result in improved clinical benefit in patients with advanced CRC with wild type RAS.



Objectives:

PART I:

1) to demonstrate 89Zr-cetuximab uptake in non-hepatic metastases at standard dose or at cohort wise increased cetuximab doses (dose escalation).

2) to determine the association between 89Zr-cetuximab uptake in non-hepatic metastases and treatment response.



PART II

To determine the response rate with an optimized dose of cetuximab as has been selected in part 1 in patients without 89Zr-cetuximab tumor uptake at standard dose of cetuximab (dose extension).



Study design: This is a multicentre non-randomized intervention study; phase I-II dose escalation/extension study.



Study population: Patients with histopathologically confirmed advanced CRC with wild type RAS, without local treatment options, aged ≥ 18 years, with a life expectancy of at least 12 weeks, who are candidates for anti-EGFR antibody monotherapy (3rd line palliative treatment).



Intervention: In the first part we will perform an exploratory PET study in patients with metastasized, RAS wild type CRC without local treatment options, who will be treated with cetuximab. We hypothesize that uptake of 89Zr-cetuximab in metastases is required for response to cetuximab. We will analyze targeting of 89Zr-cetuximab to metastases and the association between 89Zr-cetuximab tumor uptake and tumor response. Early response evaluation will be done with 18F-FDG PET. In a subgroup of 20 patients with metastasis within the field of view (18 cm) including the heart, tumor perfusion will be measured with 15O-water PET scans. In addition, we will investigate the hypothesis that increasing the cetuximab dose results in uptake in patients without uptake in metastases of 89Zr-cetuximab when cetuximab is given at the standard dose regimen. In the second part we will study whether dose adjustments based on 89Zr-cetuximab targeting results in an improved response and clinical benefit rate. In addition, EGFR expression and saturation with cetuximab is studied in tumor biopsies obtained during treatment. Molecular pathways activated by EGFR and kinase activities as well as phosphoproteomics will be studied in tumor biopsies and skin biopsies before and after start of treatment. In addition, the relation of microRNA (miRNA) and peptide profiles in relation to response to therapy will be studied.

About half of the patients with advanced CRC, RAS wild type, will respond to anti-EGFR treatment, it is unknown why not all patients benefit from this type of therapy. Although other mutations in downstream signaling molecules (e.g. B-RAF) may play a role, this does not explain it completely. We hypothesize that differences in response to cetuximab treatment is primarily due to variability in the pharmacokinetics and -dynamics of the antibody, for instance more sequestration of cetuximab in the liver resulting in a reduced amount of cetuximab available for tumor tissue.

Using PET-scan we will evaluate the 89Zr-cetuximab uptake in extra-hepatic metastases. If no uptake is present we hypothesize that these patients will not respond to the treatment. By selecting these patients and preform a dose escalation/extention we hope to improve the clinical benefit of the cetuximab treatment.

The first treatment with cetuximab will be done at day 1, at day 6 the PET-scan is made. On day 15 the second cetuximab treatment will be given, the dose depends on the first PET-scan. If dose escalation/extension takes place a second PET-scan will be done on day 21.



Hereafter a biweekly infusion of cetuximab will be given. Every 2 months a CT-scan will be performed for response evaluation (according to RECIST 1.1). The patient continues with the treatment until progressive disease, unacceptable toxicity or upon patient's request.

89Zr-cetuximab PET scan: After a therapeutic dose of cetuximab, 10mg of 89Zr-cetuximab is injected. Six days after injection a PET-scan will be made. If this scan is considerd positive, meaning uptake in extra-hepatic metastases is present, the normal dose of cetuximab will be continued.

If the first PET-scan is negative, we will increase the dose of cetuximab (3 by 3 cohort design) and repeat the PET-scan. The patient will continue the higher dose biweekly.

Furthermore we will preform a 18F-FDG PET scan and 15O-H2O PET scan, on baseline and after 2 weeks of treatment, to evaluate early changes in respectively metabolic changes and changes in tumor perfusion.

At baseline and after 3-4 week of treatment a skin biopsy and tumor biopsy will be done. We will preform oncogenic mutation analysis, we will determine EGFR expression and saturation.