Uptake and biodistribution of 89Zirconium-labeled ipilimumab in ipilimumab treated patients with metastatic melanoma

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.
We hypothesize that differences in response to treatment with ipilimumab are
due to variability in the pharmacodynamics and -kinetics of the antibody. We
hypothesize 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, we hypothesize that IRAEs are associated with high
drug levels in the affected tissue.

This study has been transitioned to CTIS with ID 2024-516547-11-00 check the CTIS register for the current data.

To assess uptake (visual and quantitative) of 89Zr-ipilimumab in tumor lesions
and biodistribution at start of nivolumab/ipilimumab therapy

Secondary
1. To determine the correlation between tumor targeting of ipilimumab and
response to therapy.
2. To assess uptake (visual and quantitative expressed as SUVmean and SUVpeak)
of 89Zr-ipilimumab in normal tissues, with special attention to gut, lung,
liver and pituitary, before start of nivolumab/ipilimumab therapy, in
nivolumab/ipilimumab treated patients and to quantitatively analyse the uptake.
3. To evaluate differences in visual uptake on PET/CT between a regular
scanner, with limited field of view, and a long axial field of view PET/CT
(total body/Quadra)
4. To determine the correlation between organ (e.g. GI-tract, skin, liver)
targeting and toxicity.
5. To determine whether tumor related pre-treatment CTLA-4 expression in CD4+ T
cells in blood of metastatic melanoma patients predicts improved survival after
ipilimumab treatment.
6. To determine the correlation between pre-treatment CTLA-4 expression in CD4+
T cells in blood of metastatic melanoma and uptake of 89Zr-ipilimumab in
tissues.
7. To determine the correlation between inflammatory infiltrate in tumor tissue
and uptake of 89Zr-ipilimumab.

Metastatic melanoma patients, who are treated with nivolumab (1 mg/kg) and
ipilimumab (3 mg/kg), will be infused with 89Zr-labeled ipilimumab one week
before injection of the first nivolumab/ipilimumab doses. Peripheral blood
mononuclear cells (PBMCs) will be collected for immunomonitoring. Metastases as
(non)-target lesions will be defined using diagnostic CT-scan. Uptake of
ipilimumab in metastases will be assessed using regions of interests (ROIs) on
89Zr-PET-scans. In part 1, an immuno-PET scan will be obtained at 72, 96 and
144 hours postinjection. In part 2, one or two immuno-PET scans will be
obtained on the same day at the optimal timepoint. All tissue concentrations of
89Zr-ipilimumab, measured by immuno-PET scan, will be related to blood
concentration. Side effects will be monitored. After 12 weeks CT-scans will be
made to assess response using RECIST 1.1 and iRECIST criteria. In addition,
patients will be followed for toxicity and survival. CTLA-4+CD4+ expression of
PBMCs and 89Zr-labeled ipilimumab uptake by tumors and organs will be
correlated with responses, toxicity and survival.
An optional tumor biopsy will be performed pre-therapy and within 48 hours
after the last immuno-PET/CT scan. Immunohistochemical analysis of the tumor
lesions will be performed. The T-lymphocyte infiltration in tumors will be
correlated to uptake of 89Zr-ipilimumab at immuno-PET scan.

Upon enrolment in this study, blood samples will be obtained for
immunomonitoring. During therapy, follow-up will include standard laboratory
analysis, immuno-PET-CT and CT-scans on regular visits to the outpatient
clinic. The radiation exposure is substantial, but acceptable in the study
population. Patients do not require shielding after injection of
89Zr-ipilimumab.