A randomized multicenter, double-blind, placebo-controlled comparison of chemotherapy plus trastuzumab plus placebo
versus chemotherapy plus trastuzumab plus pertuzumab as adjuvant therapy in patients with operable HER2-positive primary
breast cancer

Breast cancer is the most common cancer in women and the second most common
cause of cancer-related death in women worldwide. About 18% of breast cancers
overexpress HER2 and these tumors appear to be driven by HER2 signaling as they
have a poor prognosis when treated with standard chemotherapy regimens compared
to the prognosis associated with breast cancers that do not overexpress HER2.
Trastuzumab, a monoclonal antibody that binds to the extracellular domain fo
the HER-2 receptor, has been shown to reduce the risk of relapse by about 50%
and the risk of death by about 30% in HER2-positive breast cancer patients.
Pertuzumab, a monoclonal antibody that also binds to the extracellular domain
of the HER2-receptor, but a different location than trastuzumab. Pertuzumab has
also been shown to be active against HER2-positive breast cancer in patients.
Nonclinical data and pre-liminary clinical data suggests the synergic
anti-tumor activity of both type of antibodies in comination with adjuvant
standard chemotherapy (both anthracyclin and non-anthracylin-based).

The primary objective is to compare invasive disease-free survival (IDFS) in
patients with HER2-positive breast cancer randomized to chemotherapy plus one
year of trastuzumab plus placebo or chemotherapy plus one year of trastuzumab
plus pertuzumab. Secondary objectives are disease-free survival (DFS), overall
survival (OS), recurrence-free interval (RFI), distant recurrence-free interval
(DRFS), cardiac saftey, overall safety and health-related quality of life
(HRQL) in the two treated arms.

Prospective, two-arm randomized, multicenter, multinational, double-blind,
placebo-controlled study in patients with HER2-positive primary breast cancer
who have had excision (conservative surgery or total mastectomy) of their
primary tumor prior to enrollment. HER2-positive status of the primary tumor
will be confirmed by central pathology laboratory prior to enrollment of the
patient in the trial. Patients must not have received any systemic chemotherapy
or radiation therapy. The trial will consist of a screening period, a treatment
phase (chemotherapy followed by study medication), and a follow up (up to 10
years). Patients are randomized to one of the two treating arms, either
chemotherapy plus trastuzumab (8mg/kg) plus placebo OR chemotherapy plus
trastuzumab (8mg/kg) plus pertuzumab (840mg loading dose and 420mg maintanence
dose). Chemotherapy regimen varies considerably and should match the standard
of care in each centre. Patients will be in the study for 52 weeks (3-weekly
cycles). Follow-up includes 3monthly visits (first year after last dose), 6
monthly visits (during year 2 till year 5) and yearly visits (year 6 till year
10).

Chemotherapy regimen (3-8 cycles) consist of two different regimens. 1.
Anthracyclin-based regimen implicates 3 to 4 cycles of FEC (5-fluorouacil
500-600 mg/m2, epirubicin 90-120mg/m2, cyclophosphamide 500-600 mg/m2) followed
by 3 to 4 cycles of TH (docetaxel 100mg/m2, paclitaxel 80mg/m2, trastuzumab
8mg/kg). 2. Anti-anthracyclin-based regimen consist of TCH (Docetaxel 75mg/m2,
Carboplatin AUC 6, trastuzumab 8mg/kg. For details of these regimes, please see
page 6 and 7 of the protocol BIG 4-11/BO25126/TOC4939G. Study medication
(pertuzumab) starts parallel with taxane administration during chemotherapy.
Pertuzumab will be loaded at 840 mg IV and followed by 420 mg IV 3-weekly
cycles.

The following assessments are done during the study: Screening/Baseline:
Informed Consent • Submission of tumor tissue to test for HER-2 positivity •
Submission of tumor tissue for research purposes (other than HER-2 positivity
testing) • Medical history (including demographics) • Physical exam including
height (screening only) and weight • Heart function tests (ECG, ECHO or MUGA)
at screening and if necessary according to judgement of physician • Scans (CT
or MRI) and X-ray (at screening) • Blood tests (Screening and each treatment
cycle) • Blood samples for research purposes (at screening) • Medical history •
Viital signs (blood pressure, pulse, temperature) during screening and each
visit • Pregnancy test during screening and once per 3 cycles • Performance
status (questionnaire about ability to carry on daily activities) during
screening and specific visits • General health status will be performed at any
side effects that a patient has experienced • AEs / SAEs • Concomitant therapy
during Study • A small amount of pain can be experienced with both the MUGA
heart scan and bone scans when the tracer (a radioactive chemical which emits a
type of radioactivity) is injected but otherwise the test is painless • There
is a slight risk of developing an allergic reaction to the contrast material or
the tracer. The reaction can be mild (itching, rash) or severe (difficulty
breathing or sudden shock). Death resulting from an allergic reaction is rare.
Most reactions can be controlled using medication • The extra radiation
involved in the MUGA and bone scans is very small and comparable to receiving a
standard chest X-ray • During an infusion, chills, fever and other flu like
symptoms may occur. These are very common and can affect more than 1 patient in
10 • Other infusion-related symptoms are: feeling sick (nausea), vomiting,
pain, increased muscle tension and shaking, headache, dizziness, breathing
difficulties, wheezing, high or low blood pressure, heart rhythm disturbances
(palpitations, heart fluttering or irregular heart beat), swelling of the face
and lips, rash and feeling tired • Heart problems can sometimes occur during
treatment and occasionally after treatment has stopped and can be serious. They
include weakening of the heart muscle possibly leading to heart failure,
inflammation of the lining around the heart and heart rhythm disturbances.
This can lead to symptoms such as breathlessness (including breathlessness at
night), cough, fluid retention (swelling) in the legs or arms, palpitations
(heart fluttering or irregular heart beat) • Chemotherapy can possible lead to
nausea or vomiting, leucocytopenia, thrombocytopenia, fatigue, allergic
reactions (to paclitaxel), hair loss, joint pain, muscle pain, damage to nerves
of blood vessels, causing mood swings, mouth ulcers, pigmentation and cause
thrombosis • Very common side effects of trastuzumab and pertuzumab (affects
more than 1 patient in 10) are diarrhoea, weakness, skin rashes, chest pain,
abdominal pain, joint pain, muscle pain, febrile neutropenia (infection due to
low white blood cell count), mucosal inflammation (linings of the mouth,
digestive tube, nasal passages) • Other common side effects of trastuzumab and
pertuzumab (affects 1 to 10 patients in 100) are allergic reactions,
itchiness, abnormal blood counts (anaemia, low platelet count and low white
blood cell count), dry mouth and skin, constipation, dry or watery eyes,
heartburn (dyspepsia), sweating, infections including bladder and skin
infections, feeling weak and unwell, shingles, anxiety, depression, abnormal
thinking, inflammation of the breast, inflammation of the pancreas or liver,
kidney disorders, dizziness, increased muscle tone /tension (hypertonia), loss
of appetite, weight loss, tremor, numbness or tingling of the fingers and toes,
altered taste, nail disorders, hair loss, asthma, lung disorders, inability to
sleep (insomnia), sleepiness (somnolence), back pain, neck pain, bone pain,
nose bleeds, bruising, acne, haemorrhoids, leg cramps.