Randomized phase II feasibility study of Cetuximab combined with 4 cycles of TPF followed by platinum based chemo-radiation strategies

Head and neck carcinoma's account for about 6% of all cancers with an estimated
incidence around 643,000, with 351,000 deaths worldwide in 2002. Early stages
(stage I and II) achieve a 5-year disease-free survival of 80-90% with chirugie
or radiotherapy. Advanced disease (stage III and IV) can be divided into local
resectabele extended disease, irresectable locally extensive disease and
recurrent or metastatic disease. The resectabele disease patients have been
treated with surgery followed by radiotherapy. However, only 30-40% of patients
can be curated. Definitive radiotherapy has been used as a primary treatment
for large irresectable local disease but the results were poor with a 5-year
survival of about 10%. The reasons for the failure of therapy are local return
of the disease, the occurrence of distant metastases, in addition to the
occurrence of second primary tumors. These poor results of locoregional control
in the treatment of locally extensive disease has led to chemotherapy in the
treatment of this group of patients to improve.

These developments run along parallel roads. On the one hand, there is renewed
interest in induction chemotherapy with improved chemotherapy regimens prior to
the locoregional treatment. Taxanes in combination with platinum and 5FU are
more effective than platinum and 5 FU in the induction chemotherapy, measured
by response rate, time to treatment failure. Whether this results in a better
survival to the whole group is the subject of ongoing Phase III studies, for
irrecetable tumors there is a survival advantage.
Chemoradiatie with cisplatin is currently regarded as the standard treatment.
Meta analysis of phase III study show that concomitant chemoradiatie gives a
8-11% survival benefit compared to radiation alone in patients with a
non-resectable local comprehensive disease, in particular by improving the
locoregional control.

Cetuximab has added to both radiotherapy and platinum-containing chemotherapy
efficacy in this patient group show in the local advanced and in the metastatic
or recurrent setting.

The primary objective is to select one of two platinum strategies to be used in
this regimen for use as experimental arm in Phase III. This is a screening
feasibility study addressing purely investigational approaches.

The schema here under illustrates the trial design:
2 cycles of TPF will be administered. In absence of progression, patients will
be treated with 2 additional cycles of TPF. In case of SD/PR/CR after 4 cycles,
then chemoradiation will be given. If less than SD, patients will go off study.
The maximal two weeks of delay will be allowed between last cycle of TPF and
start of radiotherapy (maximal 5 weeks from the start of
last cycle of TPF treatment). All patients will receive concomitant cetuximab
at doses as explained below.
Arm 1: Induction chemotherapy with TPF followed by concomitant
chemoradiotherapy with weekly cisplatin.
Arm 2: Induction chemotherapy with TPF followed by concomitant
chemoradiotherapy with weekly carboplatin.
Both arms are given with cetuximab throughout, given with a loading dose of
400mg/m2 and then 250mg/m2 weekly.

induction chemotherapy with TPF followed by chemoradiation with weekly
cisplatin or carboplatin in combination with Cetuximab. Randomisation to
cisplatin or carboplatin.

The agents which will be given to you may have various types of side effects.
For Docetaxel, the most frequent side effect is a temporary decrease in white
blood cells
(granulocytes) which help to fight infection.
Almost all patients will experience reversible hair loss and fatigue. Skin
reactions,
low blood pressure or other allergic reactions might occur while the drug is
being given. These symptoms are reversible and will be treated if they occur.
Cisplatin and carboplatin may mostly generate myelosuppression, hearing loss
and renal functions
problems as well as neurological problems such as paresthesia, although
appearing to a lesser extend with Carboplatin
5-FU may induce oral mucositis, diarrhea, hand-foot syndrome, cardiac ischemia
and photosensibilisation.
Radiotherapy may cause redness or soreness of the skin of the irradiated area
and fatigue. It may lead to dental deterioration.
Even though Cetuximab has been given to more than 2300 patients in clinical
trials, we still need
additional studies to understand how best to use this drug. We do not know all
of the side effects of
the study drug when used alone or when it is combined with other drugs.
In other studies conducted in cancer patients and healthy volunteers treated
with Cetuximab, the
most common side effects were: rash (some look like acne), fatigue, nausea,
diarrhea, headache,
fever, dyspnea, flu symptoms and vomiting, hypomagnesemia.Other side effects
reported in these trials include: shortness of breath, difficulty in sleeping,
flatulence, stomach cramps, anemia, loss of appetite, facial flushing, mouth
ulcer, powdery taste, back pain and abnormal liver function tests.
The potential exists for infusion reactions to occur during or following
administration of cetuximab.
In clinical trials, severe hypersensitivity reactions characterized by the
rapid onset of airway
obstruction, urticaria, and/or hypotension, have been observed in 2.7% of
patients treated with
cetuximab. If it is occurred, appropriate medical therapy will be available for
use in the treatment of
such reactions.
Serious events that have been reported in 12.1% of patients include abdominal
pain, allergic reaction, asthenia, fever. They were easily controlled with
appropriate medical
therapy.
Currently amongst the Cetuximab trials (more than 2300 patients) there have
been 1 death thought
to be due to drug related toxicities/events. During the study you will
therefore be followed
extremely closely for side effects.
The effects of treatment on an embryo or fetus were evaluated in pregnant
monkeys. In this study,
Cetuximab did not cause developmental toxicity in fetuses even at maternally
toxic doses.
However, because there is no evident data in human, pregnant women cannot
participate in this
study. Also, breast-feeding is not allowed during the study as this may result
in exposure of the child to treatment.
Risks associated with drawing blood from your arm include pain, bruising,
lightheadedness, and on
rare occasions, infection. The MRI, CT and bone scans your doctor will obtain
will expose you to
small doses of radiation. For some people the dyes used for MRI, CT and bone
scans can cause an
allergic reaction.