Ipilimumab, a monoclonal antibody targeting CTLA-4, is approved for the treatment of
metastatic melanoma and significantly increases median overall survival. However, use of this
drug is associated with immune related adverse events (IRAEs) like colitis, hepatitis,
dermatitis, alveolitis and hypophysitis in 10-40% of the patients. In general IRAEs are
manageable by cessation of ipilimumab in combination with treatment with corticosteroids or
TNF-alpha blockade but they can be severe or even life-threatening. In addition, treatment
with ipilimumab is expensive. Because of the high costs and the potential serious toxicity of
ipilimumab, it is of great importance to identify biomarkers that correlate with clinical
activity and can be used to select patients that will benefit from CTLA-4 blockade therapy.
The investigators hypothesize that differences in response to treatment with ipilimumab are
due to variability in the pharmacodynamics and -kinetics of the antibody. It is hypothesized
that patients who do not respond to treatment with ipilimumab have lower drug levels in tumor
tissues as compared to patients with a good response to therapy. In addition, the
investigators hypothesize that IRAEs are associated with high drug levels in the affected
To visualize molecular interactions a novel technique is used in which positron emission
tomography (PET) is combined with labeled monoclonal antibodies. Because ipilimumab induces
activation of T-lymphocytes it is hypothesized that uptake of 89Zr-ipilimumab in tumor
lesions and normal tissue is different (i.e. higher) after the second administration of
ipilimumab (3 weeks after first injection). Therefore immuno-PET scans will be performed
after the first and after the second injection of ipilimumab.
Part one: The primary objective is:
1. To assess uptake (visual and quantitative) of 89Zr-ipilimumab in tumor lesions and
biodistribution at two timepoints (at start of ipilimumab therapy and after the second
injection 3 weeks later).
The secondary objectives are:
1. To determine the correlation between tumor targeting of ipilimumab and response to
2. To assess uptake (visual and quantitative) of 89Zr-ipilimumab in normal tissues.
3. To determine de correlation between organ targeting and toxicity