Clinical trial NCT00021255: Combination Chemotherapy With or Without Trastuzumab in Treating Women With Breast Cancer
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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Breast Neoplasms
Lead sponsor: Sanofi
Sponsor class: INDUSTRY
Collaborators: name: Cancer International Research Group (CIRG)
First posted: 2003-01-27
Enrollment: 3222
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility 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.

Primary outcomes:
measure: Percentage of Participants With Disease Free Survival at 5 Years
timeFrame: From randomization until relapse or death or up to 5 years
Secondary outcomes:
measure: Percentage of Participants With Disease Free Survival at 10 Years
timeFrame: From randomization until relapse or death or up to 10 years
measure: Overall Survival- Percentage of Participants Who Survived at 10 Years
timeFrame: From randomization until death or up to 10 years
Other outcomes:
Locations:
city: Bridgewater
country: United States
facility: Sanofi-Aventis Administrative Office
state: New Jersey
city: Buenos Aires
country: Argentina
facility: Sanofi-Aventis Administrative Office
city: Macquarie Park
country: Australia
facility: Sanofi-Aventis Administrative Office
city: Vienna
country: Austria
facility: Sanofi-Aventis Administrative Office
city: Diegem
country: Belgium
facility: Sanofi-Aventis Administrative Office
city: Sarajevo
country: Bosnia and Herzegovina
facility: Sanofi-Aventis Administrative Office
city: Sao Paulo
country: Brazil
facility: Sanofi-Aventis Administrative Office
city: Vazrjdane Region
country: Bulgaria
facility: Sanofi-Aventis Administrative Office
city: Québec
country: Canada
facility: Sanofi-Aventis Administrative Office
city: Bogota
country: Colombia
facility: Sanofi-Aventis Administrative Office
city: Zagreb
country: Croatia
facility: Sanofi-Aventis Administrative Office
city: Praha
country: Czech Republic
facility: Sanofi-Aventis Administrative Office
city: Cairo
country: Egypt
facility: Sanofi-Aventis Administrative Office
city: Tallin
country: Estonia
facility: Sanofi-Aventis Administrative Office
city: Paris
country: France
facility: Sanofi-Aventis Administrative Office
city: Frankfurt
country: Germany
facility: Sanofi-Aventis Administrative Office
city: Kallithea
country: Greece
facility: Sanofi-Aventis Administrative Office
city: Hong Kong
country: Hong Kong
facility: Sanofi-Aventis Administrative Office
city: Budapest
country: Hungary
facility: Sanofi-Aventis Administrative Office
city: Mumbai
country: India
facility: Sanofi-Aventis Administrative Office
city: Dublin
country: Ireland
facility: Sanofi-Aventis Administrative Office
city: Natanya
country: Israel
facility: Sanofi-Aventis Administrative Office
city: Milan
country: Italy
facility: Sanofi-Aventis Administrative Office
city: Seoul
country: Korea, Republic of
facility: Sanofi-Aventis Administrative Office
city: Beirut
country: Lebanon
facility: Sanofi-Aventis Administrative Office
city: Col. Coyoacan
country: Mexico
facility: Sanofi-Aventis Administrative Office
city: Macquarie Park
country: New Zealand
facility: Sanofi-Aventis Administrative Office
city: Warsaw
country: Poland
facility: Sanofi-Aventis Administrative Office
city: Bucuresti
country: Romania
facility: Sanofi-Aventis Administrative Office
city: Moscow
country: Russian Federation
facility: Sanofi-Aventis Administrative Office
city: Bratislava
country: Slovakia
facility: Sanofi-Aventis Administrative Office
city: Ljubljana
country: Slovenia
facility: Sanofi-Aventis Administrative Office
city: Gauteng
country: South Africa
facility: Sanofi-Aventis Administrative Office
city: Barcelona
country: Spain
facility: Sanofi-Aventis Administrative Office
city: Bromma
country: Sweden
facility: Sanofi-Aventis Administrative Office
city: Genève
country: Switzerland
facility: Sanofi-Aventis Administrative Office
city: Taipei
country: Taiwan
facility: Sanofi-Aventis Administrative Office
city: Megrine
country: Tunisia
facility: Sanofi-Aventis Administrative Office
city: Istanbul
country: Turkey
facility: Sanofi-Aventis Administrative Office
city: Guildford Surrey
country: United Kingdom
facility: Sanofi-Aventis Administrative Office
city: Montevideo
country: Uruguay
facility: Sanofi-Aventis Administrative Office
city: Caracas
country: Venezuela
facility: Sanofi-Aventis Administrative Office
Study officials:
affiliation: Sanofi
name: AUSSEL Jean Philippe
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.