Patient case: 55-year-old male with Melanoma. Genetic variant: NRAS (Q61K). Other conditions: Hypertension.

Clinical trial: Treatment Optimization of Cetuximab in Patients With Metastatic Colorectal Cancer Based on Tumor Uptake of 89Zr-labeled Cetuximab Assessed by PET

Summary: 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.
  The investigators hypothesize that the differences in response to treatment with cetuximab are due to variability in the pharmacokinetics and -dynamics of the antibody. Thus, the investigators hypothesize that patients who do not respond to anti-EGFR treatment, have insufficient drug levels in tumor tissue. The investigators 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. The investigators will use 89Zr-cetuximab to demonstrate tumor targeting by imaging and explore the relation of uptake with treatment response. With this approach the investigators 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.


Eligibility: Inclusion Criteria:
  -  Advanced colorectal adenocarcinoma
  -  Subjects must have been treated according to standard care with a fluoropyrimidine (e.g. fluorouracil or capecitabine), irinotecan, and oxaliplatin or had contra-indications to treatment with these drugs.
  -  Age ≥18 years.
  -  Histological or cytological documentation of cancer is required.
  -  Tumor material must be tested wild type for the K-Ras gene.
  -  Subjects have at least one measurable lesion outside the liver. Lesions must be evaluated by CT-scan or MRI according to Response Evaluation Criteria in Solid Tumors (RECIST 1.1).
  -  ECOG Performance Status of 0, 1 or 2
  -  Adequate liver and renal functions as assessed by the following laboratory requirements to be conducted within 7 days prior to screening:
  -  Total bilirubin ≤ 1.5 times the upper limit of normal
  -  ALT and AST ≤ 2.5 times upper limit of normal (≤ 5 times upper limit of normal for subjects with liver involvement of their cancer)
  -  Serum creatinin ≤ 1.5 times upper limit of normal or a calculated creatinin clearance ≥ 50 ml/min
  -  Signed informed consent must be obtained prior to any study specific procedures.
  Exclusion Criteria:
  -  Previous exposure to an anti-EGFR therapy
  -  Significant skin condition interfering with treatment
  -  Insulin dependency
  -  Pregnant or breast-feeding subjects. Women of childbearing potential must have a negative pregnancy test performed within 7 days of the start of treatment. Both men and women enrolled in this trial must agree to use adequate barrier birth control measures (e.g., cervical cap, condom, and diaphragm) during the course of the trial. Oral birth control methods alone will not be considered adequate on this study, because of the potential pharmacokinetic interaction between study drug and oral contraceptives. Concomitant use of oral and barrier contraceptives is advised. Contraception is necessary for at least 6 months after receiving study drug.
  -  Concurrent anticancer chemotherapy, immunotherapy or investigational drug therapy during the study or within 4 weeks of the start of study drug.
  -  Radiotherapy to the target lesions during study or within 4 weeks of the start of study drug. Palliative radiotherapy will be allowed.
  -  Major surgery within 28 days of start of study drug.
  -  Substance abuse, medical, psychological or social conditions that may interfere with the subject's participation in the study or evaluation of the study results.
  -  Any condition that is unstable or could jeopardize the safety of the subject and their compliance in the study.

Relevance to patient case: not relevant