Combination Chemotherapy With or Without Trastuzumab in Treating Women With Breast Cancer

• ClinicalTrials.gov Identifier: NCT00021255
• Recruitment Status: Completed
• First Posted: January 27, 2003
• Results First Posted: November 15, 2016
• Last Update Posted: November 15, 2016
• Sponsor: Sanofi
• Collaborator: Cancer International Research Group (CIRG)
• Information provided by (Responsible Party): Sanofi

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Breast Neoplasms	Drug: Doxorubicin; Drug: Cyclophosphamide; Drug: Docetaxel; Drug: Herceptin; Drug: Carboplatin	Phase 3

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 3222 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official 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
• Study Start Date: April 2001
• Actual Primary Completion Date: December 2014
• Actual Study Completion Date: December 2014

Arms and Interventions

Arm	Intervention/treatment
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.	Drug: Doxorubicin; Drug: Cyclophosphamide; Drug: Docetaxel; Other Name: Taxotere
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.	Drug: Doxorubicin; Drug: Cyclophosphamide; Drug: Docetaxel; Other Name: Taxotere; Drug: Herceptin; Other Name: Trastuzumab
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.	Drug: Docetaxel; Other Name: Taxotere; Drug: Herceptin; Other Name: Trastuzumab; Drug: Carboplatin

Outcome Measures

Primary Outcome Measures :

1. Percentage of Participants With Disease Free Survival at 5 Years [ Time Frame: From randomization until relapse or death or up to 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.

Secondary Outcome Measures :

1. Percentage of Participants With Disease Free Survival at 10 Years [ Time Frame: From randomization until relapse or death or up to 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.
2. Overall Survival- Percentage of Participants Who Survived at 10 Years [ Time Frame: From randomization until death or up to 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.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 70 Years (Adult, Older Adult)
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

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.

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.

Contacts and Locations

Locations

United States, New Jersey

Sanofi-Aventis Administrative Office

Bridgewater, New Jersey, United States, 08807

Argentina

Sanofi-Aventis Administrative Office

Buenos Aires, Argentina

Australia

Sanofi-Aventis Administrative Office

Macquarie Park, Australia

Austria

Sanofi-Aventis Administrative Office

Vienna, Austria

Belgium

Sanofi-Aventis Administrative Office

Diegem, Belgium

Bosnia and Herzegovina

Sanofi-Aventis Administrative Office

Sarajevo, Bosnia and Herzegovina

Brazil

Sanofi-Aventis Administrative Office

Sao Paulo, Brazil

Bulgaria

Sanofi-Aventis Administrative Office

Vazrjdane Region, Bulgaria

Canada

Sanofi-Aventis Administrative Office

Québec, Canada

Colombia

Sanofi-Aventis Administrative Office

Bogota, Colombia

Croatia

Sanofi-Aventis Administrative Office

Zagreb, Croatia

Czech Republic

Sanofi-Aventis Administrative Office

Praha, Czech Republic

Egypt

Sanofi-Aventis Administrative Office

Cairo, Egypt

Estonia

Sanofi-Aventis Administrative Office

Tallin, Estonia

France

Sanofi-Aventis Administrative Office

Paris, France

Germany

Sanofi-Aventis Administrative Office

Frankfurt, Germany

Greece

Sanofi-Aventis Administrative Office

Kallithea, Greece

Hong Kong

Sanofi-Aventis Administrative Office

Hong Kong, Hong Kong

Hungary

Sanofi-Aventis Administrative Office

Budapest, Hungary

India

Sanofi-Aventis Administrative Office

Mumbai, India

Ireland

Sanofi-Aventis Administrative Office

Dublin, Ireland

Israel

Sanofi-Aventis Administrative Office

Natanya, Israel

Italy

Sanofi-Aventis Administrative Office

Milan, Italy

Korea, Republic of

Sanofi-Aventis Administrative Office

Seoul, Korea, Republic of

Lebanon

Sanofi-Aventis Administrative Office

Beirut, Lebanon

Mexico

Sanofi-Aventis Administrative Office

Col. Coyoacan, Mexico

New Zealand

Sanofi-Aventis Administrative Office

Macquarie Park, New Zealand

Poland

Sanofi-Aventis Administrative Office

Warsaw, Poland

Romania

Sanofi-Aventis Administrative Office

Bucuresti, Romania

Russian Federation

Sanofi-Aventis Administrative Office

Moscow, Russian Federation

Slovakia

Sanofi-Aventis Administrative Office

Bratislava, Slovakia

Slovenia

Sanofi-Aventis Administrative Office

Ljubljana, Slovenia

South Africa

Sanofi-Aventis Administrative Office

Gauteng, South Africa

Spain

Sanofi-Aventis Administrative Office

Barcelona, Spain

Sweden

Sanofi-Aventis Administrative Office

Bromma, Sweden

Switzerland

Sanofi-Aventis Administrative Office

Genève, Switzerland

Taiwan

Sanofi-Aventis Administrative Office

Taipei, Taiwan

Tunisia

Sanofi-Aventis Administrative Office

Megrine, Tunisia

Turkey

Sanofi-Aventis Administrative Office

Istanbul, Turkey

United Kingdom

Sanofi-Aventis Administrative Office

Guildford Surrey, United Kingdom

Uruguay

Sanofi-Aventis Administrative Office

Montevideo, Uruguay

Venezuela

Sanofi-Aventis Administrative Office

Caracas, Venezuela

Sponsors and Collaborators

Sanofi

Cancer International Research Group (CIRG)

Investigators

• Study Director: AUSSEL Jean Philippe; Sanofi

More Information

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.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: Sanofi
• ClinicalTrials.gov Identifier: NCT00021255
• Obsolete Identifiers: NCT00768092
• Other Study ID Numbers: TAX_GMA_302; BCIRG 006
• First Posted: January 27, 2003
• Results First Posted: November 15, 2016
• Last Update Posted: November 15, 2016
• Last Verified: September 2016

Additional relevant MeSH terms:

Breast Neoplasms; Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Cyclophosphamide; Carboplatin; Docetaxel; Doxorubicin; Trastuzumab; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Antirheumatic Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Myeloablative Agonists; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antibiotics, Antineoplastic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Enzyme Inhibitors; Antineoplastic Agents, Immunological