Opname en biodistributie van 89Zirconium gelabeld ipilimumab in melanoompatiënten die behandeld worden met ipilimumab

Rationale:

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.

To visualize molecular interactions we use a novel technique in which positron emission tomography (PET) is combined with labeled monoclonal antibodies. Because ipilimumab induces activation of T-lymphocytes we hypothesize 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.



Objective:

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 therapy.

2. To assess uptake (visual and quantitative) of 89Zr-ipilimumab in normal tissues.

3. To determine de correlation between organ targeting and toxicity

We hypothesize that differences in response to ipilimumab treatment are due to variability in the pharmacokinetics and ¡¡ìCdynamics of the antibody. Thus, we hypothesize that patients who do not respond to CTLA-4 blockade therapy, have insufficient drug levels in tumor tissue. Because ipilimumab induces upregulation of T-lymphocytes we hypothesize 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.

- The detection of 89Zr-ipilimumab in tumor lesions (after first injection of ipilimumab) and in week 4 (after second injection of ipilimumab).

- Response after starting therapy with ipilimumab at 12 and 24 weeks and every 12 weeks thereafter.

- The detection of 89Zr-ipilimumab in normal tissue in week 1 (after first injection if ipilimumab) and in week 4 (after second injection of ipilimumab)

Metastatic melanoma patients, who are treated with ipilimumab (3 mg/kg), will be infused with 89Zr-labeled ipilimumab within 2 hours after injection of the first and second standard 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. An immuno-PET scan will be obtained at 1, 72 or 144 hours postinjection (optimal timepoint to be determined using the results of extra immuno-PET scans in the first 3 metastatic melanoma patients). All tissue concentrations of ipilimumab, measured by immuno-PET scan, will be related to blood concentration. This procedure will be repeated 3 weeks later when the patient receives the second injection of ipilimumab. Side effects will be monitored. After 12 weeks CT-scans will be made to assess response using the mWHO (modified WHO) and irRC (immune related Response Criteria) 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 after the second injection of ipilimumab. 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.