Trial Information

SHORT-HER: MULTICENTRIC RANDOMISED PHASE III TRIAL OF 2 DIFFERENT ADJUVANT CHEMOTHERAPY REGIMENS PLUS 3 VS 12 MONTHS OF TRASTUZUMAB IN HER2 POSITIVE BREAST CANCER PATIENTS

OBJECTIVES:

Primary

- To evaluate if 3 months of trastuzumab (Herceptin®) administered according to the
Finnish protocol (9-weekly administrations) is not inferior to 12 months (18
three-weekly administrations) in a standard chemotherapy protocol, in terms of
disease-free survival, in patients with HER2-positive early breast cancer.

- To determine overall survival of patients treated with these regimens.

Secondary

- To determine the failure rate at 2 years, calculated as cumulative incidence of
relapse, contralateral breast cancer (excluding in situ carcinoma), death for all
causes, and treatment withdrawal due to toxicity of therapy.

- To determine the incidence of cardiac events (defined as decrease of ejection fraction
(EF) over 15% from basal values, or decrease over 10% with EF absolute value below 50%,
or symptomatic cardiac failure, or other cardiac side effects grade 2 or more according
to NCI CTCAE v.3.

OUTLINE: This is a multicenter study. Patients are stratified according to nodal status
(positive vs negative), hormone-receptor status (estrogen receptor-positive vs progesterone
receptor-positive disease), and Regional Coordinating Center. Patients are randomized to 1
of 2 treatment arms.

- Arm I (standard long-term adjuvant treatment-12 months): Patients receive chemotherapy
comprising either doxorubicin hydrochloride IV and cyclophosphamide IV or epirubicin
hydrochloride IV and cyclophosphamide IV on day 1. Treatment repeats every 21 days for
up to 4 courses in the absence of disease progression or unacceptable toxicity.

Patients then receive paclitaxel IV over 3 hours or docetaxel* IV over 1 hour and concurrent
trastuzumab (Herceptin®) IV over 90 minutes. Treatment repeats every 21 days for up to 4
courses.

NOTE: *Patients < 65 years old receive a higher dose of docetaxel and patients ≥ 65 years
old receive a lower dose of docetaxel.

After completion of chemotherapy and concurrent trastuzumab, patients receive trastuzumab IV
over 30-60 minutes as monotherapy every 21 days for up to 14 courses in the absence of
disease progression or unacceptable toxicity.

- Arm II (experimental short-term adjuvant treatment-3 months): Patients receive
docetaxel** IV on day 1. Treatment repeats every 21 days for up to 3 courses. Patients
also receive trastuzumab IV over 30-60 minutes on day 1. Treatment repeats weekly for
up to 9 weeks (9 doses).

Within 21 days after completion of docetaxel therapy, patients receive fluorouracil IV,
epirubicin hydrochloride IV, and cyclophosphamide IV on day 1. Treatment repeats every 21
days for up to 3 courses.

NOTE: **Patients < 65 years old receive a higher dose of docetaxel and patients ≥ 65 years
old receive a lower dose of docetaxel.

In both arms, patients treated with conservative surgery or those with more than 4 positive
axillary nodes undergo radiotherapy within 8 weeks after completion of chemotherapy.
Patients enrolled in arm I undergo radiotherapy concurrently with trastuzumab.

Patients with hormone receptor-positive tumor (i.e., estrogen receptor and/or progesterone
receptor-positive tumor) also receive hormonal treatment after completion of chemotherapy.
Patients enrolled in arm I receive hormonal therapy concurrently with trastuzumab.

Premenopausal patients receive monthly luteinizing-hormone releasing-hormone agonist for 2
years plus daily tamoxifen citrate for 5 years. Post-menopausal patients receive an
aromatase inhibitor daily for 5 years.

After completion of study therapy, patients are followed for up to 3 years.