Open-label, randomised, multi-center study investigating Cetuximab, in combination with concurrent chemo- / radiotherapy in locally advanced non-small cell lung carcinoma

Lung cancer is the leading cause of cancer related death. Despite worldwide
efforts the survival has not improved much in contrast to many other types of
malignancies. In non-small cell lung carcinoma (NSCLC), as in most other
malignancies, therapy depends on the extent of the disease. Early stage
disease, without nodal metastases can be operated depending on the size and
local invasion of the tumour. Surgery alone is inadequate if lymph node
metastases are present. Thirty percent of patients present with locally
advanced NSCLC (stage IIIa and IIIb without pleural effusion). Since the early
eighties various combinations of chemotherapy (CT) and surgery, and CT and
radiotherapy (RT) with/without surgery have been tested. Both sequential (CT
followed by RT) and concurrent chemoradiotherapy (CRT) showed to be superior to
RT alone. Several comparative studies have shown that concurrent CRT is
superior over the sequential approach, however at the cost of higher albeit
acceptable toxicity. A recent meta analysis on CRT showed an absolute 3-years
overall survival benefit of 6.6% for concurrent over sequential CRT due to
improved local control.
The Epidermal Growth Factor Receptor (EGFR) is a transmembrane glycoprotein,
which is commonly expressed, in many normal human tissues. This receptor is
over-expressed on many solid tumours including NSCLC. Abnormal signalling via
this receptor has been associated with an unfavourably outcome of disease. Vice
versa, inhibition of this receptor can favourably influence tumour growth and
induce objective responses in a subset of patients, depending on clinical and
molecular parameters .
Cetuximab is a targeted therapeutic agent, a chimeric IgG1 monoclonal antibody
that specifically binds to the EGFR with high affinity, internalising the
receptor and preventing the ligands EGF and TGF-α from interacting with the
receptors and thus effectively blocking ligand-induced EGFR phosphorylation. In
addition, Cetuximab has been found to potentiate the effects of chemotherapy
and radiotherapy in experimental systems. Cetuximab (ERBITUX®) has been
approved and is available in the United States, European Union, Switzerland and
over 50 countries worldwide.

The aim of the study is to assess the feasibility of combined treatment of
Cisplatin, Cetuximab and concurrent RT and to get insight in the clinical
efficacy (for study schedule, see flow chart 1). The first phase of the study
will mainly focus on the acute toxicity. The second phase of the study, which
has a 2-arm randomised multi-centre phase 2 design, intends to assess both
safety and clinical activity of the treatment schedules.

Patients presenting at medical oncology or radiotherapy department will be
asked to participate. During the first phase of the study 12 patients will be
treated simultaneously with daily-dose Cisplatin and RT in combination with
weekly Cetuximab. This is followed by a waiting period of 3 months, between
phase 1 and before phase 2 can start, to evaluate acute toxicity. Despite the
fact that there are no major safety concerns, clear stopping rules and rules on
dose modification have been made. In the absence of major toxicity the second
phase of the study will start. In the second phase patients will be randomised
in a two-arm fashion for either, daily-dose Cisplatin, and RT, or daily-dose
Cisplatin, RT, with Cetuximab.

Patients will be asked separately to participate in a study on early response
predictors. The results of these tests will be collected prospectively and will
not influence clinical decision making.

After informed consent has been obtained the treatment plan will be finalized.
During the phase 1 part of the study, *the feasibility phase*, patients will
receive concurrent CRT in combination with Cetuximab. The second part of the
study (Phase 2) will follow if toxicity is acceptable. During this part of the
study patients will be randomised for CRT with or without Cetuximab.
The administration of study drugs should be started within 14 days after
randomisation.

Skin reactions may develop in more than 80% of patients and mainly present as
acne-like rash and/or, less frequently, as pruritus, dry skin, desquamation,
hypertrichosis, or nail disorders (e.g. paronychia). They generally resolve,
without sequelae. Approximately 15% of the skin reactions are severe, including
single cases of skin necrosis. In the event of Grade 3 or 4 skin reactions the
patients should be referred for dermatological advice.

The incidence of radiation dermatitis of any grade was comparable between the
treatment groups in a phase 3 trail in patients with squamous cell carcinoma of
the head and neck receiving RT alone (90%) or Cetuximab in combination with RT
(86%).

Other side effects observed (>=10%) in patients receiving Cetuximab monotherapy
include asthenia, dyspnoea, mucositis, nausea, pain, fever and headache.

Severe infusion-related reactions may occur (>= 1/100, < 1/10), in rare cases
with fatal outcome. They usually develop during or within 1 hour of the initial
Cetuximab infusion and may include symptoms such as rapid onset of airway
obstruction (bronchospasm, stridor, hoarseness, difficulty in speaking),
urticaria, hypotension, or loss of consciousness. In rare cases, angina
pectoris, myocardial infarction or cardiac arrest have been observed.