A phase 1 Study to Evaluate the Safety and Feasibility of Intraoperative Detection of Clear Cell Renal Cell Carcinoma Using Indium-111-DOTA-girentuximab-IRDye800CW

Accurate tumor delineation is essential in cancer management. For many types of
cancer, surgical resection is the best if not only chance for cure. Incomplete
excision of tumor tissue however negatively affects the prognosis of the
patient. Intraoperative tumor localization and resection can be enhanced using
intraoperative imaging techniques (e.g. targeted radioguided or fluorescence
guided surgery). A limitation of radioguided surgery is that it cannot provide
a precise delineation of the tumor. Fluorescence guided surgery could allow
accurate tumor delineation intraoperatively, but the penetration depth of
emitted light in tissue is limited. A powerful synergy can be achieved by
conjugating a radionuclide (e.g. Indium-111) and a fluorescent dye (e.g. IRDye
800CW) to an antibody against a tumor-associated antigen. Girentuximab
(specifically recognizes carbonic anhydrase IX) is an excellent antibody for
dual-modality image guided surgery in renal cancer in the form of
Indium-111-DOTA-girentuximab-IRDye800CW. Results of preclinical studies have
convincingly shown the potential of this targeted dual-modality approach, but
translation to the clinic has never been performed yet. Therefore, in this
study we aim to translate dual-modality image-guided surgery clinically in
order to improve tumor detection and resection.

To assess the feasibility and safety of intraoperative dual-modality imaging in
patients with renal cell carcinoma with
Indium-111-DOTA-girentuximab-IRDye800CW. Secondary objectives are to assess how
intraoperative fluorescence imaging results compare to immunohistochemical
results, to assess the pharmacokinetics of
Indium-111-DOTA-girentuximab-IRDye800CW in patients and to assess the optimal
dose of the dual-labeled antibody preparation.

This is a single center, single arm and open label study. The dual-label tracer
will be administered to twenty-two patients presenting with a primary renal
tumor or a recurrent or metastatic clear cell renal cell carcinoma lesion
scheduled for surgery. Patients receive a single intravenous dose of
Indium-111-DOTA-girentuximab-IRDye800CW. Four days after injection a SPECT/CT
scan will be acquired, and 7 days after injection the resection will be carried
out. This will be expanded with the use of dual-modality imaging
intra-operatively. During surgery the fluorescent and radioactive signal of the
primary tumor and lymph nodes will be visualized. Also, the kidney will be
examined for remnant disease. After surgery, the surgical specimens will be
investigated to determine the accumulation of
Indium-111-girentuximab-IRdye800CW in tumor tissue, surrounding normal tissue
and lymph nodes. A dose escalation study will be performed (5, 10, 30, 50 mg).
Three patients will be included per dose level. Ten additional patients will be
included in the optimal dose level.

- Day 0: Patients receive a single intravenous dose of
Indium-111-DOTA-girentuximab-IRDye800CW (100 MBq).
- Day 4 or 5 SPECT/CT images will be acquired.
- Day 7: At day 7 surgery will be planned. This will be expanded with the use
of dual-modality imaging intra-operatively. During surgery the fluorescent and
radioactive signal of the primary tumor will be visualized. Also, the kidney
will be examined for remnant disease.

The risks associated with the antibody injection are low.
Indium-111-DTPA-girentuximab has been administered to more than 100 patients
and adverse reactions have not been observed until now. Toxicity tests have
been performed with IRDye800CW in rats and no adverse reactions were seen. The
radiation dose due to the tracer injection is acceptable, because it is a
single administration of 100 MBq Indium-111 and it gives the surgeon valuable
extra information about tumor location. Patients need to undergo a SPECT/CT and
blood samples will be taken for pharmacokinetic studies. On the day of surgery
dual-modality imaging will be used intra-operatively. This will not be an extra
risk or burden to the patient as surgery will be performed conform standard of
care. Both the fluorescent camera as the gamma detector have a CE-mark and are
safe. Study participation will not give direct benefit to the single patient.
However, image-guided surgery using tumor-targeting dual-labeled antibodies
shows the potential to significantly improve oncological surgery. Therefore
this study is justified.