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Trial details imported from ClinicalTrials.gov
Ethics application status
Combination Chemotherapy With or Without Trastuzumab in Treating Women With Breast Cancer
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
Universal Trial Number (UTN)
Description of intervention(s) / exposure
Treatment: Drugs - Doxorubicin
Treatment: Drugs - Cyclophosphamide
Treatment: Drugs - Docetaxel
Treatment: Drugs - Herceptin
Treatment: Drugs - Carboplatin
Experimental: Doxorubicin+Cyclophosphamide (AC) followed by Docetaxel (AC?T) - Doxorubicin 60 mg/m² intravenous (IV) bolus injection in combination with cyclophosphamide 600 mg/m² IV bolus injection on Day 1 of every 3 weeks for 4 cycles followed by docetaxel 100 mg/m² IV infusion every 3 weeks for another 4 cycles.
Experimental: AC followed by Docetaxel + Herceptin (AC?TH) - Doxorubicin 60 mg/m² IV bolus injection in combination with cyclophosphamide 600 mg/m² IV bolus Injection on Day 1 of every 3 weeks for 4 cycles. Herceptin 4 mg/kg IV infusion on Day 1 of Cycle 5, followed by Herceptin 2 mg/kg by IV infusion weekly starting from Day 8; and docetaxel 100 mg/m² IV infusion on Day 2 of Cycle 5, then on Day 1 of every 3 weeks for all subsequent cycles ( total 4 cycles). After completion of the last cycle of chemotherapy, Herceptin 6 mg/kg IV infusion was administered every 3 weeks until 1 year from date of initial Herceptin dose.
Experimental: Docetaxel + Carboplatin + Herceptin (TCH) - Herceptin 4 mg/kg IV infusion on Day 1 of Cycle 1 only, followed by Herceptin 2 mg/kg IV infusion weekly starting from Day 8 until three weeks after the last cycle of chemotherapy. Docetaxel 75 mg/ m² IV infusion on Day 2 of Cycle 1, then on Day 1 of all subsequent cycles followed by carboplatin IV infusion at target AUC = 6 mg/mL/min repeated every 3 weeks for a total of 6 cycles. After completion of the last cycle of chemotherapy, Herceptin 6 mg/kg by IV infusion was administered every 3 weeks until 1 year from date of initial Herceptin dose.
Treatment: Drugs: Doxorubicin
Treatment: Drugs: Cyclophosphamide
Treatment: Drugs: Docetaxel
Treatment: Drugs: Herceptin
Treatment: Drugs: Carboplatin
Intervention code 
Comparator / control treatment
Primary outcome 
Percentage of Participants With Disease Free Survival at 5 Years - Disease Free Survival was defined as the interval from the date of randomization to the date of local, regional or metastatic relapse or the date of second primary cancer (with the exception of curatively treated non-melanoma skin cancer or in situ carcinoma of the cervix) or death from any cause whichever occured first. Disease free survival was estimated using the Kaplan-Meier method.
From randomization until relapse or death or up to 5 years
Secondary outcome 
Percentage of Participants With Disease Free Survival at 10 Years - Disease free survival was defined as the interval from the date of randomization to the date of local, regional or metastatic relapse or the date of second primary cancer (with the exception of curatively treated non-melanoma skin cancer or in situ carcinoma of the cervix) or death from any cause whichever occured first. Disease free survival was estimated using the Kaplan-Meier method.
From randomization until relapse or death or up to 10 years
Secondary outcome 
Overall Survival- Percentage of Participants Who Survived at 10 Years - Overall survival of the participants was measured from the date of randomization up to the date of death due to any cause. Overall survival was estimated using the Kaplan-Meier method.
From randomization until death or up to 10 years
Key inclusion criteria
- Written informed consent prior to beginning specific protocol procedures, including
expected cooperation of the participants for treatment and follow-up.
- Accessible for treatment and follow-up at participating centers.
- Histologically proven breast cancer with an interval between definitive surgery that
included axillary lymph node involvement assessment and registration of less than or
equal to 60 days. A central pathology review might be performed post randomization for
confirmation of diagnosis and molecular studies. The same block used for HER2neu
determination prior to randomization might 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).
- Participants must be either lymph node positive or high risk node negative. Lymph node
positive participants were to be defined as participants 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
participants were to be defined as participants 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, estrogen
receptor (ER) and/or progesteron receptor (PR) status was 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 left ventricular ejection fraction (LVEF)
(multiple-gated acquisition [MUGA] scan) and electrocardiogram (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) Aspartate aminotransferase (ASAT)
(Serum glutamic oxaloacetic transaminase [SGOT]) and alanine amino transferase (ALAT)
(Serum glutamic-pyruvic transaminase [SGPT]) = 2.5 UNL iii) Alkaline phosphatase = 5
UNL iv) Participants 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 creatinine was 140 -
175 µmol/L, the calculated creatinine clearance should be = 60 mL/min.
- Complete staging work-up within 3 months prior to registration. All participants had
bilateral mammography, chest X-ray (posterioanterior [PA] and lateral) and/or
computerized tomography (CT) and/or magnetic resonance imaging (MRI), abdominal
ultrasound and/or CT scan and/or MRI, and bone scan. In cases of positive bone scans,
bone X-ray evaluation was mandatory to rule out the possibility of metastatic bone
scan positivity. Other tests may be performed as clinically indicated.
- Negative pregnancy test (urine or serum) within 7 days prior to registration for all
women of childbearing potential.
- An audiology assessment with normal results was to be performed within 4 weeks of
registration. This was only for those centers who had selected cisplatin as their
platinum salt of choice for the BCIRG 006 study.
Can healthy volunteers participate?
Key exclusion criteria
- Prior systemic anticancer therapy for breast cancer (immunotherapy, hormonotherapy,
- Prior anthracycline therapy, taxoids (paclitaxel, docetaxel) or platinum salts for any
- Prior radiation therapy for breast cancer.
- Bilateral invasive breast cancer.
- Pregnant, or lactating participants. Participants of childbearing potential must
implement adequate non-hormonal contraceptive measures during study treatment
(chemotherapy and tamoxifen therapy) and must had 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 National Cancer
Institute (NCI) criteria.
- Cardiac disease that would preclude the use of doxorubicin, docetaxel and Herceptin:
1. any documented myocardial infarction
2. angina pectoris that required the use of antianginal medication
3. any history of documented congestive heart failure
4. Grade 3 or Grade 4 cardiac arrhythmia (NCI Common Terminology Criteria [CTC],
5. clinically significant valvular heart disease
6. participants 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 was =
the lower limit of normal for the radiology facility;
7. participants with poorly controlled hypertension i.e. diastolic greater than 100
mm/Hg. (Participants who were well controlled on medication were eligible for
8. participants who currently received medications (digitalis, beta-blockers,
calcium channel-blockers, etc) that altered cardiac conduction, if these
medications were administered for cardiac arrhythmia, angina or congestive heart
failure. If these medications were administered for other reasons (ie
hypertension), the participant was 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 participants treated at centers who had 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 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.
Participants must had 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
participant's potential participation in a clinical trial.
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment
Methods used to generate the sequence in which subjects will be randomised (sequence
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?
Statistical methods / analysis
Reason for early stopping/withdrawal
Accrual to date
Recruitment hospital 
Sanofi-Aventis Administrative Office - Macquarie Park
Recruitment postcode(s) 
United States of America
Bosnia and Herzegovina
Korea, Republic of
Primary sponsor type
Other collaborator category 
Cancer International Research Group (CIRG)
Ethics application status
- Compare disease-free survival in women with human epidermal growth factor receptor 2
(HER2)-neu-expressing node-positive or high-risk node-negative operable breast cancer
treated with adjuvant doxorubicin, cyclophosphamide, and docetaxel with or without
trastuzumab (Herceptin) vs trastuzumab, docetaxel, and carboplatin.
- Compare overall survival of participants treated with these regimens.
- Compare the toxic effects (including cardiac) of these regimens in these participants.
- Compare quality of life of participants treated with these regimens.
- Compare pathologic and molecular markers for predicting efficacy of these regimens in
- For substudy: Compare peripheral levels of shed HER2-neu extracellular domain with
fluorescence in situ hybridization in predicting outcome in participants treated with
Trial related presentations / publications
Slamon D, Eiermann W, Robert N, Pienkowski T, Martin M, Press M, Mackey J, Glaspy J, Chan A, Pawlicki M, Pinter T, Valero V, Liu MC, Sauter G, von Minckwitz G, Visco F, Bee V, Buyse M, Bendahmane B, Tabah-Fisch I, Lindsay MA, Riva A, Crown J; Breast Cancer International Research Group. Adjuvant trastuzumab in HER2-positive breast cancer. N Engl J Med. 2011 Oct 6;365(14):1273-83. doi: 10.1056/NEJMoa0910383.
Au HJ, Eiermann W, Robert NJ, Pienkowski T, Crown J, Martin M, Pawlicki M, Chan A, Mackey J, Glaspy J, Pintér T, Liu MC, Fornander T, Sehdev S, Ferrero JM, Bée V, Santana MJ, Miller DP, Lalla D, Slamon DJ; Translational Research in Oncology BCIRG 006 Trial Investigators. Health-related quality of life with adjuvant docetaxel- and trastuzumab-based regimens in patients with node-positive and high-risk node-negative, HER2-positive early breast cancer: results from the BCIRG 006 Study. Oncologist. 2013;18(7):812-8. doi: 10.1634/theoncologist.2013-0091. Epub 2013 Jun 28.
Perez EA, Press MF, Dueck AC, Jenkins RB, Kim C, Chen B, Villalobos I, Paik S, Buyse M, Wiktor AE, Meyer R, Finnigan M, Zujewski J, Shing M, Stern HM, Lingle WL, Reinholz MM, Slamon DJ. Immunohistochemistry and fluorescence in situ hybridization assessment of HER2 in clinical trials of adjuvant therapy for breast cancer (NCCTG N9831, BCIRG 006, and BCIRG 005). Breast Cancer Res Treat. 2013 Feb;138(1):99-108. doi: 10.1007/s10549-013-2444-y. Epub 2013 Feb 19.
Press MF, Sauter G, Buyse M, Bernstein L, Guzman R, Santiago A, Villalobos IE, Eiermann W, Pienkowski T, Martin M, Robert N, Crown J, Bee V, Taupin H, Flom KJ, Tabah-Fisch I, Pauletti G, Lindsay MA, Riva A, Slamon DJ. Alteration of topoisomerase II-alpha gene in human breast cancer: association with responsiveness to anthracycline-based chemotherapy. J Clin Oncol. 2011 Mar 1;29(7):859-67. doi: 10.1200/JCO.2009.27.5644. Epub 2010 Dec 28.
Stern HM, Gardner H, Burzykowski T, Elatre W, O'Brien C, Lackner MR, Pestano GA, Santiago A, Villalobos I, Eiermann W, Pienkowski T, Martin M, Robert N, Crown J, Nuciforo P, Bee V, Mackey J, Slamon DJ, Press MF. PTEN Loss Is Associated with Worse Outcome in HER2-Amplified Breast Cancer Patients but Is Not Associated with Trastuzumab Resistance. Clin Cancer Res. 2015 May 1;21(9):2065-74. doi: 10.1158/1078-0432.CCR-14-2993. Epub 2015 Feb 3.
AUSSEL Jean Philippe