Hepatocellular carcinoma: vascular abnormalities prior to, during and following systemic anti-cancer treatment

Despite many drugs tested in patients with advanced hepatocellular carcinoma
(HCC), progress has been limited and all patients for whom no surgical and/or
transplantation options exist will succumb of the disease. Capecitabine as one
of the few chemotherapeutic agents has demonstrated limited activity and
efficacy in patients with metastatic HCC. Sorafenib is recently registered as
the first and until now the only effective systemic therapy for patients with
HCC with Child-Pugh class A liver cirrhosis. However, currently there is no
effective systemic therapy available for patients with Child-Pugh class B of C
liver cirrosis. Therefore, exploration of novel strategies is necessary. One
of these possibilities is the use of mTOR inhibitors either alone or in
combination with cytostatic drugs, as the AKT-mTOR pathway has recently been
shown to be deregulated in most cases of HCC. Everolimus is a compound with
mTOR inhibitory activity that has been widely used in liver, heart, and renal
transplantation setting, and which now -as other mTOR inhibitors- attracts wide
attention for use in patients with metastatic malignancies. The i.v. compound
Temsirolimus, and one oral analogue everolimus (RAD001) have already
demonstrated marked activity in for instance renal cell carcinoma.

We propose a everolimus and capecitabine combination regimen in which the dose
of capecitabine will be much lower than what has been used in the treatment of
colorectal cancer, in order to allow dosing with expected mild to only moderate
side effects. In addition, the combination of two oral compounds is attractive
in terms of quality of life benefits, fewer hours spend traveling to clinics
and waiting, and no administration visits compared to i.v. chemotherapy.

To determine the efficacy of the combination of everolimus and capecitabine in
a group of patients with metastatic or locally advanced HCC with Child-Pugh
class B liver cirrhosis. In addition, to investigate biomarkers of HCC before
and during the systemic treatment.

Open label, non-placebo-controlled, non-randomized study in Advanced HCC
patients.

Everolimus will be administrated daily at an oral dose of 6 mg and the dose of
capecitabine will be 500 mg/m2 twice daily for 2 weeks, with one week of rest
period. The treatment will be continued until disease progression, unacceptable
toxicity or any other reason why continuation of the treatment is no longer in
the patient*s best interest.

not applicable