A randomized, double-blind, controlled phase III study of Stimuvax® (L-BLP25 or BLP25 liposome vaccine) in combination with hormonal treatment versus hormonal treatment alone for first-line therapy of post-menopausal women with estrogen
receptor (ER)-positive and/or progesterone receptor (PgR)-positive, inoperable locally advanced, recurrent, or metastatic breast cancer

Stimuvax® is a registered trademark of Merck KGaA. Merck KGaA has licensed
Stimuvax® (L-BLP25 or BLP25 liposome vaccine) from Biomira Inc. of Edmonton,
Alberta, Canada (now Oncothyreon Inc., Bellevue, Washington, USA).
L-BLP25 is an investigational therapeutic cancer vaccine developed for use as
an active specific immunotherapy against MUC1-expressing malignant tumors.
Details of the physical, chemical, and pharmaceutical properties; the
nonclinical studies, and efficacy and safety in humans are summarized in the
Investigator*s Brochure (IB) [1].

3.1 Introduction
3.1.1 Epidemiology of Breast Cancer
Breast cancer (BRCA) is the most common form of cancer in women worldwide,
accounting for 32% of all female cancers [2], and represents a major public
health problem due mainly to its high incidence, excess mortality, and multiple
therapeutic challenges. To date, more than 1.2 million women are diagnosed with
BRCA each year worldwide, and more than 320,000 will succumb to this disease.
The incidence rates of BRCA are exceedingly high, especially in the European
Union, Australia, and the United States of America (USA) with respective rates
of 67.4, 71.7, and 86.3 per 100,000 [2, 3].
It is estimated that more than 182,460 women will be diagnosed with BRCA and
that
40,480 will die from it in the USA alone this year [2]. In Europe, an estimated
429,000 breast cancer-specific deaths occurred in 2006 [3]. Approximately 75%
to 80% of newly diagnosed patients are women with early stage BRCA. Despite the
use of chemotherapy or hormonal therapy (HT), many of these patients will die
as a result of local recurrence that is not amenable to surgery, or of
metastatic disease. The outlook for metastatic BRCA is bleak, with five-year
survival rates averaging 25% to 26% [4]. These alarming facts call for the
development of more effective therapeutic strategies for BRCA.

3.1.2 Management of Breast Cancer
Management of BRCA has been difficult. Treatment of early BRCA has established
a gold standard (combined modality therapy with surgery plus radiotherapy,
followed by adjuvant chemotherapy, HT, or biologic therapy) for most women,
with reasonable gains in terms of reduction of risk of recurrence (i.e.,
five-year recurrence rates of 15.1% and 26.5% for tamoxifen-treated and
control, respectively), and overall reduction of risk of mortality (five-year
mortality rates of 8.3% and 11.9% for tamoxifen-treated and control,
respectively) [5].
Unlike early BRCA, there is no standard of care for women who present with
inoperable locally advanced, recurrent, or metastatic disease (herein referred
to as advanced BRCA). Because advanced BRCA is an incurable disease, treatment
is largely palliative in nature and is aimed at improving quality of life
(QOL), and prolonging survival. Endocrine therapy is now widely accepted as
treatment modality of choice for women with hormonesensitive estrogen
receptor-positive (ER+) and/or progesterone receptor-positive (PgR+) disease
(approximately 70% of patients) [6]. Such treatment is aimed at blocking
estrogen from binding to its ligand in the tumors or at reducing estrogen
biosynthesis.
For more than two decades, the anti-estrogen drug tamoxifen has been the drug
of choice for women with ER+ or "ER-unknown" advanced BRCA. By blocking the
binding of estrogen to its receptor, tamoxifen prevents estrogen-signaling
through the ER and, consequently, induces tumor shrinkage and reduces tumor
growth, resulting in response rates of 21% to 40% and time to progression (TTP)
of approximately six to eight months [7, 8, 9]. However, a significant number
of women have a disease that is tamoxifen-refractory, or will become
tamoxifen-resistant during therapy. Furthermore, long-term use of tamoxifen is
associated with the risk of developing endometrial cancer [7, 8, 9]. These
observations have fueled the search for alternative approaches to inhibit the
estrogen stimulus to hormone-sensitive tumors.
Aromatase inhibitors (AIs) have emerged as attractive pharmacological agents
and effective alternatives to tamoxifen for front-line or second-line endocrine
therapy of advanced BRCA. These drugs cause tumor shrinkage by reducing
systemic levels of estrogen via inhibition of aromatase, a cytochrome
P450-dependent enzyme. A new generation of AIs, anastrozole and letrozole, have
been used with great success in frontline endocrine therapy for
hormone-sensitive advanced BRCA. Several randomized studies have demonstrated
the superior efficacy of these agents over tamoxifen in women with ER+, PgR+,
or "hormone receptor unknown" advanced BRCA.
Two large randomized studies supported the superior efficacy of anastrozole for
front-line therapy of post-menopausal women with hormone receptor-positive or
"hormone receptor unknown" advanced BRCA [7, 8]. In the first study, Nabholtz
et al. observed anastrozole to be as effective as tamoxifen in terms of
response rate (21% and 17%, respectively) an TTP (medians 11.1 and 5.6 months,
respectively; p = 0.09, with a hazard ratio (HR) of tamoxifen:anastrozole of
1.44) [7]. Treatment was generally well tolerated, with subjects in the
tamoxifen arm developing more thromboembolic events (8.2%) and vaginal bleeding
(3.8%). In the second study, Bonneterre et al. found anastrozole to be as
effective as tamoxifen (median TTP of approximately eight months for both arms,
generally similar response rates of 32.9% and 32.6%, respectively) [8]. Again,
tamoxifen induced more thromboembolic events and vaginal bleeding.
The efficacy and tolerability of letrozole was evaluated in one large
multicenter, doubleblind study that randomized women with hormone
receptor-positive or "hormone receptor unknown" advanced BRCA to either
letrozole or tamoxifen. Letrozole demonstrated significantly superior efficacy
over tamoxifen in terms of response rate (32% vs. 21%, respectively) and TTP
(median 9.4 months and 6.0 months, respectively) [9]. Additionally, letrozole
demonstrated a slight survival advantage by extending median survival by 4
months over that of tamoxifen (34 months vs. 30 months, respectively).
Treatment was generally well tolerated in both groups, with tamoxifen patients
having the same incidence of thromboembolic events as those administered
letrozole.
Overall, the two AIs showed superior efficacy relative to tamoxifen, and thus,
they have become a standard of care for women with ER+ and PgR+ advanced BRCA.
As can be seen from these results of HT studies in advanced BRCA, the main goal
of extending survival in this disease remains largely unfulfilled. Furthermore,
combined modality therapies that include potent anti-neoplastic drugs (e.g.,
vinca alkaloids, antimicrotubule agents, and DNA intercalating agents) and
rationally designed targeted novel agents (herceptin, lapatinib) have all
proven to be effective anticancer drugs when used alone or in combination with
HT [10]. However, their limited effect on survival and increased toxicity
highlight the urgent need for novel therapeutic strategies, such as cancer
immunotherapy, that aim to improve the clinical outcome of BRCA patients
treated with vaccines, antibodies, or immunomodulatory agents.
One of the most important advances in the field of cancer immunotherapy is the
identification of tumor antigens that could be successfully used to target
tumor cells. The mucin MUC1 is one of the most studied antigens expressed by
BRCA cells. Its characterization and the identification of the core repeat
peptide (20-mer repeated peptide) as a major T-cell immunogen has allowed the
development of several vaccines that are under intensive investigation for
therapy of BRCA [11, 12]. L-BLP25 is a MUC1-based vaccine consisting of a
25-mer synthetic peptide (encompasses the core repeated peptide) into a
liposomal formulation. Previous phase I and II studies have established its
immunogenicity in patients with refractory non-small cell lung cancer (NSCLC)
and hormone-naïve prostate cancer [13].
One of the recent advances with L-BLP25 is the observation of a strong survival
trend in favor of L-BLP25 in a subgroup of NSCLC patients with locoregional
stage IIIB disease [14]. These results are encouraging and have served as the
impetus for the current study. This phase III study proposes to use L-BLP25 as
an add-on therapy to either tamoxifen or either of the two AIs (anastrozole,
letrozole) to assess the treatment effect, focusing primarily on the ability of
L-BLP25 to improve survival (measured asprogression-free survival [PFS])
afforded by HT alone.

Primary
Demonstration of superior efficacy (as measured by PFS time) of L-BLP25 in
combination with hormonal treatment (HT) over placebo plus HT, when used for
first-line therapy of hormone receptor-positive (ER+ and/or PgR+), inoperable
locally advanced, recurrent, or metastatic breast cancer (BRCA).

Secondary
• Safety and Tolerability;
• Overall Survival (OS) Time;
• Objective Tumor Response;
• Duration of Response;
• Clinical Benefit;
• Time to Progression (TTP);
• Time to Chemotherapy;
• Quality of Life (QOL);
• Healthcare Resource Utilization (HRU);
• Serum CA 15-3.

Randomized (2:1), double-blind, controlled, multicenter, multinational, safety
and eff

Randomized (2:1), double-blind, controlled, multicenter, multinational, safety
and efficacy study of HT with or without L BLP25.

Investigational product:
• A single I.V. infusion of 300 mg/m2 (to a maximum of 600 mg) of
cyclophosphamide will be administered 3 days prior to the first L-BLP25
vaccination.
• Subjects will then receive eight consecutive subcutaneous vaccinations with
1,000 mg L-BLP25 at weeks 1, 2, 3, 4, 5, 6, 7 and 8, followed by maintenance
vaccinations (1,000 mg L-BLP25) at six-week intervals, beginning at week 14,
and continuing until PD is documented or the subject discontinues for any other
reason.

Participation in this study has the risk on the following side effects:

The pre-treatment dose of cyclophosphamide or saline can cause nausea. Your
doctor can give you drugs to help overcome any nausea you may feel. In previous
clinical trials with cyclophosphamide given prior to Stimuvax injections, about
half of the patients said they felt mild nausea, and the other half did not
experience any side effects. Because the pre-treatment is given through a vein,
some discomfort or bruising might occur at the site of the needle insertion.
The injection of Stimuvax or the placebo can cause some discomfort. In
addition, you may notice some temporary itching, swelling or redness at the
sites of injections. In some cases, you may feel a lump at the injection sites.
You may also experience some mild flu-like symptoms like fatigue, nausea,
headache, fever and muscle pain for a few days after the injections.
As with any drug, it is possible that an allergic reaction to a study treatment
drug could occur. This may result in a rash, a drop in blood pressure, or
difficulty in breathing.
This is unlikely to happen, and when it occurs, it often starts within an hour
of the injection. This is the reason why you must wait at the clinic for one
hour after the injection so that a doctor is available in case emergency
treatment is required.
As Stimuvax is similar to a substance made naturally by your cancer cells,
there is a possibility you may develop an *autoimmune disorder* like rheumatoid
arthritis or lupus, although this has never, thus far, been reported.
There is also a risk of discomfort, bruising, and possible infection as the
result of drawing blood for laboratory testing.
Stimuvax contains a so-called adjuvant, a component that enhances the activity
of Stimuvax. Cases of brain and spinal cord inflammation and autoimmune
diseases have been reported with products containing a component of the
adjuvant along with a component of this vaccine. The relationship of the
product under study or its components to these events is unknown. Evaluation of
these and similar events continues.
The side effects listed above may be temporary, long-lasting or permanent.
However, most of these side effects are reversible, that is, they will stop
once the drug is discontinued.
Treatment with these drugs and procedures performed may have also other risks
that have not yet been identified. If you have any side effects, either those
mentioned above or others, or if you want more information on how the drug(s)
may affect you, you should talk with the doctor or study nurse in charge of the
study. Their contact telephone numbers are on the last page of this Subject
Information Sheet.

CT-Scans
You will have extra CT (Computer Tomography)/Isotope scans (modern techniques
that allow more detailed assessment of the size of your cancer) during the
study that would not be part of normal care. This will mean you are exposed to
very slightly more radiation than normal, and there is a tiny theoretical risk
to your future health.

In addition to the risks listed above, there may be risks or side effects that
are unexpected or unknown at this time.