START * Stimulating Targeted Antigenic Responses To NSCLC A multi-center phase III randomized, double-blind placebo-controlled study of the cancer vaccine Stimuvax® (L-BLP25 or BLP25 liposome vaccine) in non-small cell lung cancer (NSCLC) subjects with unresectable stage III disease

Lung cancer continues to be the most common cancer in the world, both in terms
of
incidence (1.2 million new cases or 12.3% of the world total) and mortality
(1.1 million deaths or 17.8% of the world total) (2, 3, 4). Worldwide, lung
cancer is by far the most common cancer among men (17% of all new cancers in
2000) with the highest rates observed in North America, Europe (especially
eastern Europe), South America, and Australia/New Zealand. Moderately high
rates are also seen in parts of eastern Asia. In less developed regions the
highest rates are seen in the Middle East, China, the Caribbean, South Africa,
Zimbabwe, and the Pacific. In 2000, lung cancer was reported to be the number
one cancer among men in southern and eastern Europe, Western and southeastern
Asia, as well as Micronesia/Polynesia. In females, the incidence rates are much
lower
worldwide (the rate is 11.1 per 100,000 in women compared with 34.9 per 100,000
in men). The highest estimated rates are in northwestern Europe and North
America, where in the year 2000 lung cancer was the fourth most frequent cancer
of women. Moderately high rates are also seen in Australia, New Zealand and
China (2, 3, 4). In North America, lung cancer remains the leading cause of
cancer death for both men and women in 2004. Although breast cancer and
prostate cancer have the highest incidence rate, lung cancer remains the most
frequent cause of death from cancer. In 2004, an estimated 21,700 new cases of
lung cancer will be diagnosed in Canada and 173,770 new cases in the United
States (US). In the same year, an estimated 18,900 deaths are anticipated from
lung cancer in Canada and 160,440 deaths in the US (5, 6).
Non-small cell lung cancer (NSCLC) is the most common type of lung cancer,
accounting for about 80% of all cases (7). The majority of NSCLC subjects
present with advanced disease at diagnosis and a large number of those
diagnosed with early stage disease eventually experience recurrent disease (8).
Chemotherapy and radical radiotherapy have become the standard of care for
unresectable stage III NSCLC, but even with this aggressive approach the median
survival is often less than two years with only 15% surviving five years (8).
Analyses of phase III trials of chemotherapy for advanced NSCLC demonstrate
improvements in survival and quality of life, although the absolute gains have
been small (9, 10, 11). Given the considerable toxicity and modest benefit of
chemotherapy for NSCLC, it is apparent that additional therapies
A variety of treatment strategies have been evaluated in recent years in an
effort to improve outcomes for patients with advanced NSCLC. Studies evaluating
the addition of gefitinib (12, 13), erlotinib (14, 15), or trastuzumab (16) to
standard platinum based chemotherapy regimens as well as studies on maintenance
therapy with vinorelbine (17) for patients with stable disease or an objective
response following first line chemotherapy, have shown limited success. Even
with combined modality treatment, median survival rates, ranging from
approximately 13 to 27 months for unresectable stage III disease, indicate much
room for improvement (18, 19, 20). While immunologic approaches have not
yielded important advances in disease control to date, there is a growing body
of
literature describing the potential of immunotherapy. Much of the focus on
cancer
immunotherapy has been in the area of cancer vaccine development, particularly
with the identification of specific antigens associated with cancer (21).
L-BLP25 is a cancer vaccine that targets the exposed core peptide of the MUC1
tumorassociated antigen. Recent studies have identified that MUC1 is associated
with cellular transformation as demonstrated by tumorigenicity (22) and can
confer resistance to genotoxic agents (23). High level cell surface expression
(24, 25), reported immunosuppressive activities of its released ectodomain
(26), and anti-adhesive properties (27, 28) all contribute to this mucin's
ability to protect and promote tumor cell growth and survival and make MUC1 an
attractive target for cancer immunotherapy.
Currently, there are no recommended treatment options for unresectable stage
III NSCLC patients who are stable or responding following primary
chemo-radiotherapy. Preliminary survival results from a previous L-BLP25 study
(B25-LG-304) performed in stage IIIB and IV NSCLC patients show the greatest
treatment effect in survival to be in stage IIIB locoregional (LR) patients
(see Section 3.5.3). Based on these results, L-BLP25 may have potential as a
maintenance therapy for unresectable stage III NSCLC patients.

Primary objective:
* To compare survival duration of all randomized subjects by treatment arm.
Secondary objectives of this trial are to compare all randomized subjects by
treatment arm for:
* Time to symptom progression (TTSP) as measured by the Lung Cancer Symptom
Scale (LCSS).
* Time to progression (TTP) as determined by the investigator.
* One-, two- and three-year survival.
* Safety.

A multi-center phase III randomized, double-blind placebo-controlled study in
subjects with unresectable stage III NSCLC who have demonstrated either stable
disease or objective response following primary chemo-radiotherapy (concomitant
or sequential). Subjects will be randomized 2:1 either to L-BLP25 drug product
(hereinafter "LBLP25") (investigational arm) or to L-BLP25 placebo
(hereinafter "placebo")respectively.
Subjects will be stratified by:
* Disease stage (IIIA versus IIIB).
* Response to primary chemo-radiotherapy (stable disease versus objective
response).
* Type of primary chemo-radiotherapy (concomitant versus sequential).
* Region (1: North America [Canada, United States] and Australia, 2: Western
Europe, or 3: Rest of World [Mexico, Central and South America, Eastern Europe
and Asia]).
Periodic evaluations of the trial data will be conducted by an independent Data
Monitoring Committee (DMC) to ensure subject safety and the validity and
scientific merit of the study.

Hiervoor verwijzen wij graag naar de flowchart in het protocol (pagina 108-109)
en pagina 56 (6. Treatments)

In the 2 weeks preceding the study, the doctor will record the medical history
of the patient and will do a physical examination, including vital functions. A
blood sample will be taken to determine the general condition and to confimr
that the patient can start the study. Part of this sample will be kept to do
additional testing. Possibly, an x-ray, CT-scan, bone scan or other medical
imaging tests can be done to determine the tumor size. A brain (CT- or
MRI-scan) scan must be performed to exclude metastases to the brain. With the
help of an ECG, the condition of the heart will be determined. The doctor will
inform the patient about the x-rays or scans that are required. the patient
will be asked to fill out 2 questionnaires about the quality of life. During
the study, information will be collected regarding the working condition
(currently employed or not), the use of health resources (e.g.
hospitalisations, visit to the doctor and medication) for patients who are
participating to this study.

Before an injection (Stimuvax or placebo) is administered, the patient will get
a single dose of another drug, either cyclophosfamide or a saline solution,
depending on the treatment group to which the patient is assigned.

Is has been shown that the effects of Stimuvax of letting the immune system
work against the cancer, is increased if a low dosis of cyclophosfamide is
administered before Stimuvax is administered. The saline solution will not have
an effect on the body. The cyclofosphfamide or saline solution will be
administered once through an infusion with a needle in the arm. The patient
will get this treatment during a visit to the day clinic.
3 days after the pre-treatment, the patient will get 7 additional treatments
with Stimuvax or the placebo: 1, 2, 3, 4, 5, 6 and 7 weeks after the first
treatment. Each treatment consists of 4 small injections with either Stimuvax
or placebo, under the skin of the upper arm of abdomen. Each visit will take
about 2 hours and an inspection of the injection site will be done, together
with the monitoring of the vital functions, during maximum 1 hour after the
injections.
during the visit in week 4 an additional blood sample will be taken, to
determine the general health. The patient will also undergo a physical
examination.
During the visits in week 2, 5 and 8 and during the 6-weekly visits, the
patient will complete 2 questionnaires about the quality of life.
1 week after the eight treatment with Stimuvax or placebo, a physical
examination will be done to determine the effect of the treatments on the
patient. A new blood sample will be drawn to determine the general condition
and to do additonal testing afterwards.
Of the doctor feels that the patient will continue to benefit from the
treatments, the injections will be continued. the maintenance injections will
be given every 6 weeks, beginning at week 13. Each 2nd treatment visit a new
blood sample will be
drawn.
The dose cyclophosfamide or saline during the pre-treatment can cause nausea.
The doctor can prescribe medication to take away this nausea. Because the
pre-treatment is administered through a vein, some discomfort or bruising is
possible at the injection site.
The injection with Stimuvax or placebo can cause some discomfort. Itching,
swelling or redness can temporarily cause some discomfort. In some cases, a
lump is felt on the injection sites. You could also have flue-like symptoms
during a couple of days after the injections.
As with all drugs, an allergic reaction can happen. This can lead to rash,
blood pressure drop, difficulty breathing.