Efficacy and feasibility of the combination of everolimus and capecitabine in patients with metastatic or locally advanced pancreatic carcinoma

Pancreatic cancer accounts for only 3% of all malignancies in the western
world, but is one of the leading causes of cancer-related mortality. Over the
past 30 years many chemotherapeutic drugs have been evaluated as treatment for
patients with pancreatic cancer, but tumour control with the current available
systemic chemotherapy is disappointing. At present, gemcitabine is widely
accepted as the standard chemotherapy for patients with pancreatic cancer, with
a modest objective response rate of 11%, but a substantial impact on clinical
benefit rate. Despite this advantage, there is need for a different approach to
attack this highly aggressive and resistant form of cancer resulting in a
prolonged survival of patients with inoperable/ metastatic pancreatic cancer.

The phosphatidylinositol 3*-kinase (PI3K)/Akt pathway is important for cell
growth and survival and is often dysregulated in cancer. Akt is activated
downstream of PI3K and can activate several effector proteins, including
mammalian target of rapamycin (mTOR). Dysregulation of mTOR signaling occurs in
a wide variety of human tumours, including pancreatic cancer. Thus, mTOR might
therefore be a promising objective of novel molecular targeting therapy for
pancreatic cancer. Indeed, a couple of pre-clinical studies with mTOR
inhibitors demonstrated promising results and adding chemotherapy improved the
efficacy even more. However, a recently published phase I study demonstrated
unacceptable toxicity of the combination everolimus and gemcitabine. Therefore,
in our study we have chose to add capecitabine, a chemotherapeutic drug with
the same objective response activity in patients with metastatic pancreatic
cancere, to the mTOR inhibitor.

The primary objective of this study is to determine the efficacy and
feasibility of the combination of everolimus and capecitabine in a group of
patients with metastatic or locally advanced pancreatic cancer.

Everolimus seems the most attractive mTOR inhibitor because of the favourable
pharmacokinetic profile and possibility of oral administration. Everolimus will
be administrated daily at a dose of 9 mg, devided into 2 doses. Capecitabine is
an orally administered fluoropirimidine. The dose will be 1000 mg/m2 twice
daily for 2 weeks, with one week rest period.

Everolimus will be administrated daily at a dose of 9 mg, devided into 2 doses.
Capecitabine is an orally administered fluoropirimidine. The dose will be 1000
mg/m2 twice daily for 2 weeks, with one week rest period.

Each cycle contains 3 weeks, in which the patients take everolimus daily and
capecitabine the first 2 weeks. At day 1 of every cycle the patient will come
to the hospital for blood investigations and evaluation of the toxicity
profile. After 3 cycles (9 weeks) during the treatment fase a CTscan will be
performed to establish response.
The expected adverse events of everolimus are nausea, vomiting, rash, fatigue,
anorexia, hyperlipidemia, hyperglycaemia, diarrhoea, elevation of
transaminases, headache and stomatitis. During the first 2 weeks of the study
patients will be treated with everolimus alone, to monitor everolimus induced
toxicity. In case of grade 3 or 4 toxicity patients will be excluded from the
trial and there will be no further treatment with everolimus.
The most common reported side effects of capecitabine are: diarrhoea, nausea
and vomiting, stomatitis, anorexia, hand-foot syndrome, fatigue, elevated
bilirubine levels and bone marrow suppression.
If the combination of everolimus and capecitabine will result in increased
adverse evnets is unknown and will be investigated in this study.