Rationale: 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 epidermal growth factor receptor (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.