A multicenter, open-label, single-arm study of pertuzumab in combination with trastuzumab and a taxane in first line treatment of patients with HER2- positive advanced (metastatic or locally recurrent) breast cancer

Breast cancer is the most common cancer in women, with a global prevalence of
more than 1 million patients and an annual mortality rate of approximately
450,000 deaths (American Cancer Society). While improved early detection and
advances in systemic therapy for early stage disease have resulted in a small
decline in breast cancer mortality since 1989, metastatic breast cancer (MBC)
remains largely incurable with a median survival of approximately 24 months
(National Cancer Institute, www.seer.cancer.gov). Factors associated with poor
survival include age * 50 years, visceral disease, shorter disease-free
interval, aneuploid tumors, tumors with a high S-phase fraction, p53
accumulation, low
bcl-2 expression, negative hormone receptor status, and positive human
epidermal growth factor receptor 2 (HER2) status (Chang 2003).

Although the treatment of MBC is palliative rather than curative in intent,
improvement in survival is an important treatment goal. There is a significant
need for new agents with novel mechanisms of action and non-overlapping
toxicity, which can be combined with established treatment for breast cancer.

Evidence suggests that dysregulation of ligands and receptors of the HER family
are important in the pathogenesis of cancer. The HER tyrosine kinase receptor
family is comprised of four receptors: HER1 (epidermal growth factor receptor
[EGFR]), HER2, HER3, and HER4. These receptors mediate tumor cell growth,
survival, and differentiation (Sundaresan et al. 1999; Yarden and Sliwkowski
2001). HER receptors normally exist as inactive monomers. Activation of HER
receptors occurs following ligand binding, leading to receptor dimerization and
cell signaling through the PI3-kinase/AKT pathway for promotion of tumor cell
survival and through the mitogen-activated protein kinase pathway for cellular
proliferation. HER2 has no known ligand and, in a state of overexpression, can
form active homodimers and initiate tyrosine kinase signaling without ligand
stimulation. Additionally, as HER2 concentrations increase, the incidence of
HER2 interactions with other receptors is also increased, resulting in a broad
recruitment of a number of proteins (Jones et al. 2006). Recent data obtained
using micro-array technology suggest that the HER2 receptor can bind to more
than 17 different proteins and may recruit proteins that other HER receptors
cannot recruit. These activities highlight the promiscuity of HER2 in its
ability to bind to other HER receptors and initiate tyrosine kinase signaling
through several mechanisms (Jones et al. 2006).

Approximately 18-25% of patients overexpress HER2. Overexpression of HER2 in
breast cancer has been correlated with high histologic grade, increased mitotic
activity, p53 mutation, negative estrogen receptor (ER) status, absence of
bcl2, and absence of lobular architecture. Despite associations with other
known negative prognostic factors, HER2 overexpression has been independently
associated with poorer disease-free survival and overall survival (OS) compared
with tumors that do not overexpress HER2 (Pauletti et al. 2000). Approximately
65% of breast cancers are ER-positive and progesterone receptor-positive
(American Cancer Society).

The objective of this study is to investigate the safety and efficacy of
pertuzumab in combination with standard therapy, trastuzumab and a taxane.

This study is an open-label, single-arm, multicenter Phase IIIb study to
evaluate the safety and tolerability of pertuzumab in combination with
trastuzumab and a taxane. Patients with HER2-positive advanced breast cancer
(metastatic or locally recurrent) who have not previously received systemic
non-hormonal anticancer therapy in the metastatic setting are eligible to
participate in the study. Approximately 1500 patients will be enrolled into the
study in approximately 250-300 centers worldwide. Details of the treatment are
given in Section 4.3. Patient will receive study medication until unacceptable
toxicity, withdrawal of consent, disease progression, or death whichever occur
first.

End of study: All patients will continue to be followed up until at least 60
months after the last patient has been enrolled into the study or all patients
in the study have withdrawn consent, or died, whichever occurs first.

Pertuzumab will be administered as an intravenous infusion on Day 1 of the
first treatment cycle as a loading dose of 840 mg, followed by 420 mg on Day 1
of each subsequent 3 weekly cycle. Pertuzumab will be administered first.

Initial infusions of pertuzumab will be administered over 60 (± 10) minutes and
patients observed for a further 60 minutes from the end of infusion for
infusionassociated symptoms such as fever, chills etc. Interruption or slowing
of the infusion may reduce such symptoms. If the infusion is well tolerated,
subsequent infusions may be administered over 30 (± 10) minutes, with patients
observed for a further 30 minutes.

The most common adverse events (also known as side-effects) reported as related
to pertuzumab and trastuzumab are:
* Diarrhea is reported by approximately 67% of patients
* Neutropenia (a reduction in white blood cells, which are needed to fight
infection) occurs in about half of patients and can be serious, especially if
accompanied by fever. Anemia (a lack of red blood cells) occurs in about a
quarter of patients.
* Symptoms such as nausea, fever, diarrhea, chills, shortness of breath,
fatigue, rash and headache have been observed in between about 20% to 40% of
patients. They were in general mild to moderate but may occur as an allergic
reaction on the same day as the infusion in approximately 20% of patients and
can, very rarely, be severe (anaphylaxis).
* Mucosal inflammation (inflammation of the lining of the mouth,
gastrointestinal or genital tract), decreased appetite, vomiting, an abnormal
sense of taste, disorders of the nails, asthenia (physical weakness and lack of
strength) or aching of the muscles or joints may occur in about 20% to 30% of
patients.
* Colds or chest infections and dry and/ or itchy skin (pruritus) can occur in
around 15% of patients.
Less frequently, some patients developed heart failure (inadequate pumping of
the heart) whilst having trastuzumab and/or pertuzumab treatment. In many
cases, this was due to the fact that they had been treated with trastuzumab in
combination with certain other chemotherapy drugs (called doxorubicin or
epirubicin).

The following problems may be caused by taxanes such as docetaxel, paclitaxel,
or nab-paclitaxel:
* Alopecia (hair loss) and edema (swelling) of the ankles and feet.
* Neutropenia (reduction in white blood cells) usually occurring 7 days after
the infusion.
* Allergic reactions such as fever, chills, hypotension (low blood pressure),
shortness of breath, headache, flushing and rashes. These reactions usually
occur during the first or second infusion within minutes. They are in general
mild to moderate.
* Peripheral neuropathy (numbness, tingling and pain in the fingers and toes).
* Nausea, vomiting, constipation or diarrhea.
* Pain and swelling at the injection site and the surrounding veins.