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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT00021255




Registration number
NCT00021255
Ethics application status
Date submitted
11/07/2001
Date registered
27/01/2003
Date last updated
15/11/2016

Titles & IDs
Public title
Combination Chemotherapy With or Without Trastuzumab in Treating Women With Breast Cancer
Scientific title
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
Secondary ID [1] 0 0
BCIRG 006
Secondary ID [2] 0 0
TAX_GMA_302
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Breast Neoplasms 0 0
Condition category
Condition code
Cancer 0 0 0 0
Breast

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
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.
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Percentage of Participants With Disease Free Survival at 5 Years
Timepoint [1] 0 0
From randomization until relapse or death or up to 5 years
Secondary outcome [1] 0 0
Percentage of Participants With Disease Free Survival at 10 Years
Timepoint [1] 0 0
From randomization until relapse or death or up to 10 years
Secondary outcome [2] 0 0
Overall Survival- Percentage of Participants Who Survived at 10 Years
Timepoint [2] 0 0
From randomization until death or up to 10 years

Eligibility
Key inclusion criteria
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 = 10 g/Dl

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.
Minimum age
18 Years
Maximum age
70 Years
Sex
Females
Can healthy volunteers participate?
No
Key exclusion criteria
Exclusion criteria:

* Prior systemic anticancer therapy for breast cancer (immunotherapy, hormonotherapy, chemotherapy).
* Prior anthracycline therapy, taxoids (paclitaxel, docetaxel) or platinum salts for any malignancy.
* 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], version 2.0)
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 entry)
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 years
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.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
1/04/2001
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
1/12/2014
Sample size
Target
Accrual to date
Final
3222
Recruitment in Australia
Recruitment state(s)
Recruitment hospital [1] 0 0
Sanofi-Aventis Administrative Office - Macquarie Park
Recruitment postcode(s) [1] 0 0
- Macquarie Park
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
New Jersey
Country [2] 0 0
Argentina
State/province [2] 0 0
Buenos Aires
Country [3] 0 0
Austria
State/province [3] 0 0
Vienna
Country [4] 0 0
Belgium
State/province [4] 0 0
Diegem
Country [5] 0 0
Bosnia and Herzegovina
State/province [5] 0 0
Sarajevo
Country [6] 0 0
Brazil
State/province [6] 0 0
Sao Paulo
Country [7] 0 0
Bulgaria
State/province [7] 0 0
Vazrjdane Region
Country [8] 0 0
Canada
State/province [8] 0 0
Québec
Country [9] 0 0
Colombia
State/province [9] 0 0
Bogota
Country [10] 0 0
Croatia
State/province [10] 0 0
Zagreb
Country [11] 0 0
Czech Republic
State/province [11] 0 0
Praha
Country [12] 0 0
Egypt
State/province [12] 0 0
Cairo
Country [13] 0 0
Estonia
State/province [13] 0 0
Tallin
Country [14] 0 0
France
State/province [14] 0 0
Paris
Country [15] 0 0
Germany
State/province [15] 0 0
Frankfurt
Country [16] 0 0
Greece
State/province [16] 0 0
Kallithea
Country [17] 0 0
Hong Kong
State/province [17] 0 0
Hong Kong
Country [18] 0 0
Hungary
State/province [18] 0 0
Budapest
Country [19] 0 0
India
State/province [19] 0 0
Mumbai
Country [20] 0 0
Ireland
State/province [20] 0 0
Dublin
Country [21] 0 0
Israel
State/province [21] 0 0
Natanya
Country [22] 0 0
Italy
State/province [22] 0 0
Milan
Country [23] 0 0
Korea, Republic of
State/province [23] 0 0
Seoul
Country [24] 0 0
Lebanon
State/province [24] 0 0
Beirut
Country [25] 0 0
Mexico
State/province [25] 0 0
Col. Coyoacan
Country [26] 0 0
New Zealand
State/province [26] 0 0
Macquarie Park
Country [27] 0 0
Poland
State/province [27] 0 0
Warsaw
Country [28] 0 0
Romania
State/province [28] 0 0
Bucuresti
Country [29] 0 0
Russian Federation
State/province [29] 0 0
Moscow
Country [30] 0 0
Slovakia
State/province [30] 0 0
Bratislava
Country [31] 0 0
Slovenia
State/province [31] 0 0
Ljubljana
Country [32] 0 0
South Africa
State/province [32] 0 0
Gauteng
Country [33] 0 0
Spain
State/province [33] 0 0
Barcelona
Country [34] 0 0
Sweden
State/province [34] 0 0
Bromma
Country [35] 0 0
Switzerland
State/province [35] 0 0
Genève
Country [36] 0 0
Taiwan
State/province [36] 0 0
Taipei
Country [37] 0 0
Tunisia
State/province [37] 0 0
Megrine
Country [38] 0 0
Turkey
State/province [38] 0 0
Istanbul
Country [39] 0 0
United Kingdom
State/province [39] 0 0
Guildford Surrey
Country [40] 0 0
Uruguay
State/province [40] 0 0
Montevideo
Country [41] 0 0
Venezuela
State/province [41] 0 0
Caracas

Funding & Sponsors
Primary sponsor type
Commercial sector/industry
Name
Sanofi
Address
Country
Other collaborator category [1] 0 0
Other
Name [1] 0 0
Cancer International Research Group (CIRG)
Address [1] 0 0
Country [1] 0 0

Ethics approval
Ethics application status

Summary
Brief summary
Primary objective:

* 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.

Secondary objective:

* 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 these participants.
* For substudy: Compare peripheral levels of shed HER2-neu extracellular domain with fluorescence in situ hybridization in predicting outcome in participants treated with these regimens.
Trial website
https://clinicaltrials.gov/study/NCT00021255
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, Pinter T, Liu MC, Fornander T, Sehdev S, Ferrero JM, Bee 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.
Press MF, Sauter G, Buyse M, Fourmanoir H, Quinaux E, Tsao-Wei DD, Eiermann W, Robert N, Pienkowski T, Crown J, Martin M, Valero V, Mackey JR, Bee V, Ma Y, Villalobos I, Campeau A, Mirlacher M, Lindsay MA, Slamon DJ. HER2 Gene Amplification Testing by Fluorescent In Situ Hybridization (FISH): Comparison of the ASCO-College of American Pathologists Guidelines With FISH Scores Used for Enrollment in Breast Cancer International Research Group Clinical Trials. J Clin Oncol. 2016 Oct 10;34(29):3518-3528. doi: 10.1200/JCO.2016.66.6693.
Public notes

Contacts
Principal investigator
Name 0 0
AUSSEL Jean Philippe
Address 0 0
Sanofi
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries



Summary Results

For IPD and results data, please see https://clinicaltrials.gov/study/NCT00021255