Multicenter Phase III Randomized Trial Comparing Doxorubicin and Cyclophosphamide Followed By Docetaxel (AC-T) With Doxorubicin and Cyclophosphamide Followed By Docetaxel and Trastuzumab (Herceptin)(AC-TH) and With Docetaxel, Carboplatin and Trastuzumab (TCH) In The Adjuvant Treatment Of Node Positive and High Risk Node Negative Patients With Operable Breast Cancer Containing The HER2 Alteration
- Histologically proven breast cancer with an interval between definitive surgery that
includes axillary lymph node involvement assessment and registration of less than or
equal to 60 days. A central pathology review may be performed post randomization for
confirmation of diagnosis and molecular studies. The same block used for her2neu
determination prior to randomization may be used for the central pathology review.
- Definitive surgical treatment must be either mastectomy with axillary lymph node
involvement assessment, or breast conserving surgery with axillary lymph node
involvement assessment for operable breast cancer (T1-3, Clinical N0-1, M0). Margins
of resected specimen from definitive surgery must be histologically free of invasive
adenocarcinoma and/or ductal carcinoma in situ (DCIS).
- Patients must be either lymph node positive or high risk node negative. Lymph node
positive patients will be defined as patients having invasive adenocarcinoma with at
least one axillary lymph node (pN1) showing evidence of tumor among a minimum of six
resected lymph nodes. High risk lymph node negative patients will be defined as
patients having invasive adenocarcinoma with either 0 (pNo) among a minimum of 6
resected lymph nodes or negative sentinel node biopsy (pNo) AND at least one of the
following factors: tumor size > 2 cm, ER and/or PR status is negative, histologic
and/or nuclear grade 2-3, or age < 35 years.
- Tumor must show the presence of the her2neu gene amplification by Fluorescence
In-Situ Hybridization (FISH analysis) by a designated central laboratory.
- Estrogen and/or progesterone receptor analysis performed on the primary tumor prior
to randomization. Results must be known at the time of randomization.
- Karnofsky Performance status index ≥ 80%.
- Normal cardiac function must be confirmed by LVEF (MUGA scan) and ECG within 3 months
prior to registration. The result of the MUGA must be equal to or above the lower
limit of normal for the institution.
- Laboratory requirements: (within 14 days prior to registration)
a) Hematology: i) Neutrophils ≥ 2.0 109/L ii) Platelets ≥ 100 109/L iii) Hemoglobin ≥
b) Hepatic function: i) Total bilirubin ≤ 1 UNL ii) ASAT (SGOT) and ALAT (SGPT) ≤ 2.5
UNL iii) Alkaline phosphatase ≤ 5 UNL iv) Patients with ASAT and/or ALAT > 1.5 x UNL
associated with alkaline phosphatase > 2.5 x UNL are not eligible for the study.
c) Renal function: i) Creatinine ≤ 175 µmol/L (2 mg/dL) ii) If limit reached, the
calculated creatinine clearance should be ≥ 60 mL/min.
- Complete staging work-up within 3 months prior to registration. All patients will
have bilateral mammography, chest X-ray (PA and lateral) and/or CT and/or MRI,
abdominal ultrasound and/or CT scan and/or MRI, and bone scan. In cases of positive
bone scans, bone X-ray evaluation is mandatory to rule out the possibility of
metastatic bone scan positivity. Other tests may be performed as clinically
- Negative pregnancy test (urine or serum) within 7 days prior to registration for all
women of childbearing potential.
- An audiology assessment with normal results will be performed within 4 weeks of
registration. This is only for those centers who have selected cisplatin as their
platinum salt of choice for the BCIRG 006 study.
- Prior systemic anticancer therapy for breast cancer (immunotherapy, hormonotherapy,
- Prior anthracycline therapy, taxoids (paclitaxel, docetaxel) or platinum salts for
- Prior radiation therapy for breast cancer.
- Bilateral invasive breast cancer.
- Pregnant, or lactating patients. Patients of childbearing potential must implement
adequate non-hormonal contraceptive measures during study treatment (chemotherapy and
tamoxifen therapy) and must have negative urine or serum pregnancy test within 7 days
prior to registration.
- Any T4 or N2 or known N3 or M1 breast cancer.
- Pre-existing motor or sensory neurotoxicity of a severity ≥ grade 2 by NCI criteria.
- Cardiac disease that would preclude the use of doxorubicin, docetaxel and Herceptin:
1. any documented myocardial infarction
2. angina pectoris that requires the use of antianginal medication
3. any history of documented congestive heart failure
4. Grade 3 or Grade 4 cardiac arrhythmia (NCI CTC, version 2.0)
5. clinically significant valvular heart disease
6. patients with cardiomegaly on chest x-ray or ventricular hypertrophy on ECG,
unless they demonstrate by MUGA scan within the past 3 months that the LVEF is ≥
the lower limit of normal for the radiology facility;
7. patients with poorly controlled hypertension i.e. diastolic greater than 100
mm/Hg. (Patients who are well controlled on medication are eligible for entry)
8. patients who currently receive medications (digitalis, beta-blockers, calcium
channel-blockers, etc) that alter cardiac conduction, if these medications are
administered for cardiac arrhythmia, angina or congestive heart failure. If
these medications are administered for other reasons (ie hypertension), the
patient will be eligible.
- Other serious illness or medical condition:
1. history of significant neurologic or psychiatric disorders including psychotic
disorders, dementia or seizures that would prohibit the understanding and giving
of informed consent
2. active uncontrolled infection
3. active peptic ulcer, unstable diabetes mellitus
4. impaired hearing (only for those patients treated at centers who have selected
cisplatin as their platinum salt of choice)
- Past or current history of neoplasm other than breast carcinoma, except for:
1. curatively treated non-melanoma skin cancer
2. in situ carcinoma of the cervix
3. other cancer curatively treated and with no evidence of disease for at least 10
4. ipsilateral ductal carcinoma in-situ (DCIS) of the breast
5. lobular carcinoma in-situ (LCIS) of the breast
- Current therapy with any hormonal agent such as raloxifene, tamoxifen, or other
selective estrogen receptor modulators (SERMs), either for osteoporosis or
prevention. Patients must have discontinued these agents prior to randomization.
- Chronic treatment with corticosteroids unless initiated > 6 months prior to study
entry and at low dose (≤ 20 mg methylprednisolone or equivalent).
- Concurrent treatment with ovarian hormonal replacement therapy. Prior treatment must
be stopped prior to randomization.
- Definite contraindications for the use of corticosteroids.
- Concurrent treatment with other experimental drugs. Participation in another clinical
trial with any investigational not marketed drug within 30 days prior to study entry.
- Concurrent treatment with any other anti-cancer therapy.
The above information is not intended to contain all considerations relevant to a
patient's potential participation in a clinical trial.