A Phase I safety, toxicity and biomarker study of peri-operative sorafenib treatment in patients undergoing radiofrequency ablation (RFA) for liver metastases of colorectal cancer

Colorectal cancer is the second leading cause of cancer related deaths in the
western world with it*s incidence still rising. Death from colorectal cancer is
caused by metastatic disease rather than by the primary tumour (Boyle et al,
2004; Ponz de Leon et al, 2004). About 50% of patients with colorectal cancer
are destined to develop hepatic metastases. Liver surgery offers the only hope
for cure for colorectal liver metastases with a 5 year survival rate between
20-50%. Unfortunately, only 20% of patients are eligible for partial liver
resection due to localization, number or size of the metastases or insufficiënt
hepatic parenchymal reserve. Patients with non-resectable or non-resected liver
metastases of colorectal cancer survive for only 8-12 months without any
treatment. Median overall survival after radiofrequency ablation (RFA) is 30
months. Local tumor destruction by RFA has emerged as a safe and effective
treatment modality for patients with colorectal liver metastases that are
irresectable. RFA is a technique in which heat is locally generated leading to
tumour destruction with only minimal concomitant damage to surrounding liver
parenchyma. RFA is considered a safe technique with the ability to accomplish
local disease control as shown in a large population of patients. The overall
survival is between 40 and 53% at 3 years. Reported complication rates range
from 7.1 to 9.8% The overall survival is between 40 and 53% at 3 years. A
downside of RFA is the recurrence rate , with local recurrence rates varying
from 0 - 60% A hypoxic microenvironment, generated by RFA, seems to be an
ideal microenvironment for tumor cells to grow In ischemic tissue, HIF-1alpha
is stabilized which induces tumor neovascularization through upregulation of
VEGF (Carmeliet et al, 1998; Brahimi-Horn et al, 2001). VEGF is one of the most
potent downstream effectors of HIF 1-alfa and plays a pivotal role in the
stimulation of hypoxia driven angiogenesis. Angiogenesis is a prerequisite for
metastatic progression. The aim of this study is to incorporate the VEGFR
inhibitor sorafenib in the treatment with RFA. Cancer progression greatly
depends on the formation of new blood vessels in order to supply the tumor of
oxygen, nutrients and growth factors (Zhang Y, 2007; Folkman et al, 2002).
Furthermore, it facilitates tumour dissemination. Neovascularization can occur
by proliferation of endothelial cells, or by mobilization of bone
marrow-derived endothelial progenitor cells, which migrate and incorporate into
growing vessels (Ribatti, 2004). In 9 patients treated with RFA that were in
included in the UMC Utrecht liver database we found a rise in the number of
EPC*s as soon as 2 hours RFA treatment. (Nijkamp et al, unpublished
observations)

- To asses the safety and toxicity of peri-ablative sorafenib given in doses of
either 200 mg or 400 mg twice daily.
- To asses the effect of perioperative sorafenib on the RFA induced
mobilization of endothelial progenitor cells and cytokines involved in the
process of angiogenesis
-To assess the effect of perioperative sorafenib on DFS after RFA.

This is a phase I study to assess the safety and toxicity of peri-ablative
sorafenib treatment. Furthermore, this study will assess if peri-opertive
sorafenib administration prevents mobilization of bone marrow derived
endothelial progenitor cells as a result of radiofrequency ablation (RFA) for
patients with liver metastases of colorectal cancer.

Patients must fulfill all the inclusion/exclusion criteria to be eligible for
the study.
Sorafenib treatment will start 7 days before RFA by taking sorafenib 200 mg
tablets twice daily.

Cohort 1: Sorafenib: dose level 200 mg (1 tablet) twice daily until progression
occurs or until 6 months of treatment, whatever occurs first.
Cohort 2: Sorafenib: dose lever 400 mg (2 tablets) twice daily until
progression occurs or until 6 months of treatment, whatever occurs first
Blood collection for measurement of EPC*s and cytokines will be done
pre-sorafenib treatment, pre-ablative treatment, 20 min, 2, 4, 24 hours after
RFA.
CT chest, 4 phase CT abdomen will be made before RFA, 2 weeks after RFA,
thereafter
every 6 months after RFA. This is the standard follow up after RFA

Cohort 1 and 2 can be extended until 12 patients if advense events occure which
are not related to Sorafenib or RFA. The Principal Investigators will decide
whether cohorts wil be extended and report this to the Medical Ethical
Committee of the UMC Utrecht.

Radiofrequency ablation

Liver regeneration and wound heeling.
Both VEGF receptor 2 (VEGFR2) and VEGFR1 mediate functions on endothelial cells
and other cell types that mediate wound heeling and liver regeneration.
There are no clinical studies reporting the effect of sorafenib on wound
heeling and liver regeneration. In a preclinical study where PTK/ZK, a compound
that inhibits all VEGF receptors was administered to mice before and after RFA,
there were no problems with wound heeling and liver regeneration encountered
(vd Bilt et al. 2006 unpublished results)
Tetrogenicity:
Sorafenib is an antiangiogenic compound that in animal studies has shown to be
highly teratogenic and to induce embryo fatal toxicity. Therefore only patients
using an effective method of birth control will be included.
Adverse events:
Most common side-effects of sorafenib are: hand-foot skin reaction and rash,
usually limited to grade 1 and 2.
Hypertension: blood pressure should be monitored the first 6 weeks.
Most reported side effects in clinical studies were mild to moderate and
manageable.
Gastrointestinal perforation is a very uncommon event, occurring in less than
one percent of patients. Haemorrhage: An increased risk of bleeding is
reported. The incidence of grade 3 and 4 bleeding events is 2% for patients
treated with sorafenib compared to placebo.