A phase I/II Study to Evaluate the Safety and Feasibility of Dual-modality imaging using Indium-111-DOTA-labetuzumab-IRDye800CW in patients with Peritoneal Carcinomatosis of Colorectal Origin

In patients with peritoneal carcinomatosis (PC) of colorectal origin and no
evidence of disease outside the peritoneal cavity, survival can be improved by
complete cytoreductive surgery (CRS) and Hyperthermic Intraperitoneal
Chemotherapy (HIPEC). Unfortunately, conventional imaging studies cannot
reliably assess the degree of intraperitoneal tumor extension. Therefore,
patient selection for HIPEC can only be done accurately by abdominal inspection
during surgery. Up to 13% of patients are considered inoperable during surgery
. Due to the presence of adhesions and scar tissue in the peritoneal cavity of
these patients (often as result of previous surgery), tumor deposits may be
difficult to detect with the naked eye and/or palpation. Sensitive
preoperative imaging may help to select patients eligible for CRS and HIPEC.
Once selected for surgery patients* prognosis depends on the completeness of
cytoreductive surgery, which may be improved using intraoperative imaging. The
dual-labeled anti-CEA antibody labetuzumab, 111In-labetuzumab-IRDye800CW,
enables both preoperative SPECT/CT imaging to assess the intraperitoneal tumor
load preoperatively, as well as intraoperative fluorescence imaging to detect
and visualize tiny tumor deposits during surgery. Labetuzumab is a humanized
monoclonal antibody specifically directed against carcinoembryonic antigen
(CEACAM5), which is overexpressed in approximately 95% of colorectal cancers
(CRC). Four or five days after administration of this tracer a SPECT/CT scan
can be acquired to determine the intraperitoneal cancer extension.
Subsequently, the fluorescent (IRDye800CW) signal can be used during
cytoreductive surgery to detect and visualize tumor nodules.

Primary objectives: To assess the feasibility, accuracy and safety of
preoperative SPECT/CT and intraoperative fluorescence imaging after
administration of 111In-labetuzumab-IRDye800CW in patients with PC of
colorectal origin who will undergo cytoreductive surgery and HIPEC.

Secondary objectives: To assess whether additional malignant lesions can be
visualised by fluorescence imaging after cytoreductive surgery , to assess the
correlation between localization of the dual-labeled antibody and CEA
expression in tumor and healthy tissue, and to determine the gross blood
clearance of 111In-labetuzumab-IRDye800CW in patients.

This is a single centre, open label, single arm intervention study. Patients
will receive a single intravenous dose of 111In-labetuzumab-IRDye800CW (100
MBq). A protein dose escalation study will be performed to assess the optimal
dose of the dual-labeled antibody for intra-operative dual-modality imaging.
The first 15 patients will receive a single intravenous dose of 2, 10 or 50 mg
of 111In-labetuzumab-IRDye800CW. Five patients per dose level will be
included. After assessment of the optimal dose, the 14 following patients will
receive the lowest dose that still has optimal fluorescence imaging
characteristics.
At day 4 or 5 after antibody injection a SPECT/CT scan will be acquired and the
peritoneal carcinomatosis index (PCI) will be scored by two independent
observers.
One or two days after the SPECT/CT scan patients will undergo standard surgical
resection of intraperitoneal tumors extended with the use of fluorescence
imaging and image-guided surgery. After completion of the surgical resection,
the peritoneal cavity will be examined for residual tumor tissue by
fluorescence imaging and additional suspected tumor lesions may be removed
after critical appreciation of the surgeon on malignant aspect. Subsequently
the patient will undergo a standard of care HIPEC procedure. After surgery, the
surgical specimens will be analyzed microscopically, immunohistochemically (CEA
expression) and by gamma counting to quantitatively determine the uptake of the
radiolabeled antibody. Adverse events will be monitored and and estimation of
blood clearance of the tracer will be determined by taking blood samples at
different time (moments of least possible patient burden) points after
injection.

The risks associated with the antibody injection are negligible. Radiolabeled
labetuzumab preparations have been administrated to more than 100 patients at
doses up to 100 mg per patient without significant or clinically relevant
toxicity, except for mild allergic reactions. Toxicity tests in rats and mice
have been performed with IRDye800CW and IRDye800CW-conjugated antibodies and no
adverse reactions were seen. In non-human primates a small increase of
QTc-interval was seen after administration of cetuximab-IRDye800CW. This was
considered to be a cetuximab-mediated effect and no QTc-prolongation has been
observed in clinical trials with IRDye800CW-conjugated girentuximab or
bevacizumab (currently more than 70 patients at the Radboud UMC and UMC
Groningen).
Patients will undergo a thoraco-abdominal body SPECT/CT scan and three 3 ml
blood samples will be taken to monitor safety (blood chemistry, liver and
kidney function) and to determine the intravenous dose. Effective radiation
dose of a 100 MBq 111In*labeled IgG: labetuzumab-IRDye800CW will be 22 mSv, the
total dose calculated for the surgeon is 180 µSv per year (index yeardose
0.18). Considering the patient category (metastatic CRC) this is considered an
acceptable dose according to the ICRP 62. On the day of surgery fluorescence
imaging will be used intraoperatively. This will not be an extra risk or burden
to the patient. Image-guided surgery using tumor-targeting dual-label
antibodies could significantly and clinically relevantly improve oncological
surgery, justifying this study.