Pre-operative Administration of Anti-EGFR Monoclonal Antibodies (cetuximab) for the Eradication of Circulating Tumor Cells in Patients Undergoing Curative Treatment of Colorectal Liver Metastases; a dose finding study

One of the most frequent complications of colorectal cancer is the development
of liver metastases, which results in high morbidity and mortality. Previously,
we showed in animal models that abdominal surgery (necessary to remove the
tumor) enhances the risk of liver metastases development. This is due to the
concomitant inflammatory response, which induces vascular changes in the liver,
allowing the adherence of circulating tumor cells (CTCs). Unfortunately, most
patients have CTCs at the time of surgery. Moreover, the presence of CTCs is
correlated with poor survival of patients with primary colorectal cancer as
well as patients with resectable liver metastases. Thus, we hypothesize that
also in patients resection of the primary tumor or liver metastases promotes
implantation and metastases of CTCs. Importantly, we recently demonstrated that
pre-operative anti-tumor monoclonal antibody (mAb) therapy resulted in
efficient antibody-dependent phagocytosis of tumor cells by liver macrophages
(Kupffer cells). Moreover, mAb therapy prevented outgrowth of liver metastases
in animal models. We therefore now propose to pre-operatively treat patients
that are scheduled for surgical treatment (with curative intent) of colorectal
liver metastases with the anti-epidermal growth factor receptor (EGFR) mAb
cetuximab, as EGFR is expressed in up to ~80% of colorectal carcinoma. We
anticipate that pre-operative cetuximab therapy will lead to a reduction in the
number of CTCs, which may ultimately decrease the risk of (recurrent)
metastases development.

The main objective of this study is to determine whether a single neoadjuvant
gift of anti-EGFR mAb, administered 48 hours prior to local treatment of
colorectal liver metastases, reduces the number of CTCs. Secondary endpoints
are determination of the minimal effective dose of cetuximab, the ability of
patient plasma samples to induce growth inhibition and antibody-dependent
phagocytosis of tumor cells, level of EGFR expression of CTCs, the immune
profile, patient RAS mutation status, and disease free survival.

We will perform a dose-finding study to establish the lowest dose of cetuximab
that effectively removes tumor cells from the circulation. We will conduct
this first trial in patients that are scheduled for (surgical) treatment of
colorectal cancer liver metastases with curative intent.

Patients will receive a single dose of cetuximab 48 hours prior to surgery in a
dose escalating fashion. Starting dose is 50mg/m2 and this will be increased to
100mg/m2, 200mg/m2, and 400mg/m2 in consecutive cohorts depending on whether
the minimal effective dose is determined.

Cetuximab is currently widely used in the clinic in e.g. metastatic head and
neck squamous cell carcinoma and colorectal carcinoma with a mild to moderate
adverse events profile. In these settings cetuximab is used at an initial dose
of 400 mg/m2 followed by weekly doses of 250 mg cetuximab per m2. With this
treatment schedule, the predominant side effects of cetuximab include skin
reactions, which occur in about 80% of patients, hypomagnesaemia which occurs
in approximately 10% of patients and infusion-related reactions, which occur
with mild to moderate symptoms in about 10% of patients and with severe
symptoms in 1% of patients. Side effects of cetuximab in our study are expected
to be less frequent and less severe as most patients in our study will be
treated with a lower dose, which will be administered only once. As stated
above, we hypothesize that eradicating CTCs will ultimately lead to reduced
outgrowth of metastasis in colorectal cancer patients. As metastases of
colorectal cancer (and all malignancies in general) contribute greatly to
morbidity and mortality, reduction of metastases formation greatly benefits
cancer patients.