A phase I/ II, non-randomized, feasibility/ safety and efficacy study of the combination of everolimus, cetuximab and capecitabine in patients with metastatic pancreatic cancer

Pancreatic cancer patients have one of the worst prognoses among all cancer
types with a 5 year survival rate of less than 5%. Despite significant changes
during the last decade in our molecular knowledge on this disease, the
prognosis and management of pancreatic cancer have remained unchanged.
Although epidermal growth factor receptor (EGFR) mutation is rare in pancreatic
cancer (2-4%), overexpression of EGFR occurs in at least one-half of all
pancreatic cancers and correlates with a poor prognosis. Recently several
studies explored the activity of epidermal growth factor receptor (EGFR)
inhibitors in patients with pancreatic cancer. But, in spite of its biological
background, EGFR inhibitors have no or only modest clinical activity in
pancreatic cancer. One of the mechanisms responsible for this observation will
be the presence of other activated pathways. Therefore, the best change of
success will be realized when using a combination of agents that inhibit
separate pathways known to be critical to the survival of the tumour. Combining
a monoclonal antibody against the EGFR and inhibition of the phosphoinositide
3-kinase (PI3K) pathway account for potential candidates of the above
combinatorial approaches since they inhibit both the upstream and downstream
mediators of the same signal transduction pathways. Indeed, pre-clinical data
suggest that combined inhibition of the PI3K pathway (via its downstream
effector protein mTOR) and EGFR is synergistic in anti-cancer activity, can
prevent upregulation of the PI3K pathway and restore EGFR resistance to EFGR
inhibitors.
There is a strong rationale to combine targeted therapy with classical
cytotoxic drugs. For pancreatic cancer gemcitabine would be the drug of choice,
but a phase I study demonstrated severe bone marrow toxicity by the combined
mTOR inhibition and gemcitabine (already at the gemcitabine dose level of 600
mg /m2). Therefore in our study we will add the chemotherapeutic agent
capecitabine. In addition to the rationale combining targeted with cytotoxic
therapy, there is another argument to choose this cytotoxic agent. Thymidine
phosphorylase (TP) is the key enzyme in the metabolic conversion of 5-FU to its
active cytotoxic form, thereby enhancing 5-FU cytotoxicity. On the other hand
TP promotes tumour angiogenesis by enzymatic conversion of thymidine into dRib.
Since it has been demonstrated that mTOR inhibition can block dRib, combining
the mTOR inhibitor everolimus and capecitabine can therefore counteract this
TP-based escape mechanism under 5-FU treatment.

In this study we want to determine the activity and safety of concurrent
interruption of the MAPK and PI3K pathways by EGFR and mTOR inhibition in
patients with metatastatic pancreatic cancer

This phase I/II non randomized single center study will be performed as a two
step design. Part I is dose finding, whereby dose escalations will be performed
for everolimus and capeciatbine. Part II is the efficacy study. At the MTD
doses in part II biomarker studies will be performed in blood and tumor tissue.

Study design phase I part:
The first week patients will be treated with everolimus alone. Capecitabine
will be administered for 14 days in a 3 weekly cycle, starting on day 8.
Cetuximab will be administered weekly, starting at day 8. The dose is fixed for
cetuximab during study treatment, whereas the doses of everolimus and
capecitabine will differ per dose level.

First dose level:
Everolimus 5 mg daily continuously, Capecitabine 600 mg/m2 bid for 2 weeks
every 3 weeks, Cetuximab 400mg/m2 (120 min infusion) first dose, thereafter 250
mg/m2 (60 min infusion) weekly.
Second dose level:
Everolimus 10 mg daily continuously, Capecitabine 600 mg/m2 bid for 2 weeks
every 3 weeks, Cetuximab 400mg/m2 (120 min infusion) first dose, thereafter 250
mg/m2 (60 min infusion) weekly.
Third dose level:
Everolimus 10 mg daily continuously, Capecitabine 800 mg/m2 bid for 2 weeks
every 3 weeks, Cetuximab 400mg/m2 (120 min infusion) first dose, thereafter 250
mg/m2 (60 min infusion) weekly.


Study design phase II part

At the MTD 14-25 patients with pancreatic cancer will be included.
In the phase II part, everolimus will be administered during one week before
start of cetuximab. At day 8 the first dose of cetuximab will be administered.
Capecitabine will be started one week thereafter. This enables us to perform
pharmacodynamic studies to assess biomarker changes during the different phases
of treatment.

Everolimus will be administered continuously in a dose of 5 or 10 mg orally
once daily (dependent on MTD from part 1).
Capecitabine will be administered orally in a dose of 400 - 800 mg/m2 twice
daily for 14 days followed by one week rest (dependent on MTD from part 1).
Patients will receive cetuximab infusions via an infusion pump, with an initial
dose of 400 mg/m² (over 120 min) and subsequent weekly infusions of 250 mg/m²
(over 60 min), starting day 8.

Everolimus will be administered continuously in a dose of 5 or 10 mg orally
once daily (dependent on MTD from part 1).
Capecitabine will be administered orally in a dose of 400 - 800 mg/m2 twice
daily for 14 days followed by one week rest (dependent on MTD from phase I).
Patients will receive cetuximab infusions via an infusion pump, with an initial
dose of 400 mg/m² (over 120 min) and subsequent weekly infusions of 250 mg/m²
(over 60 min), starting day 8.

Each cycle contains 3 weeks, in which the patients take everolimus daily and
capecitabine the first 2 weeks, followed by one week rest. Cetuximab will be
administred via an infusion pump weekly. At various days during treatment 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, bone marrow suppression, lung toxicity, headache and stomatitis.
The most common reported side effects of capecitabine are: diarrhoea, nausea
and vomiting, stomatitis, anorexia, hand-foot syndrome, fatigue and bone marrow
suppression. Adverse events of cetuximab are skin reaction and infusion related
reactions.