Clinical trial NCT00312208: Docetaxel in Breast Cancer
Official title: A Multicenter Phase III Randomized Trial Comparing Docetaxel in Combination With Doxorubicin and Cyclophosphamide Versus Doxorubicin and Cyclophosphamide Followed by Docetaxel as Adjuvant Treatment of Operable Breast Cancer HER2neu Negative Patients With Positive Axillary Lymph Nodes
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Breast Cancer
Lead sponsor: Sanofi
Sponsor class: INDUSTRY
Collaborators: name: Cancer International Research Group (CIRG)
First posted: 2006-04-07
Enrollment: 3299
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 :

* To compare disease-free survival after treatment with docetaxel in combination with doxorubicin and cyclophosphamide to doxorubicin and cyclophosphamide followed by docetaxel in operable adjuvant breast cancer HER2neu negative patients with positive axillary lymph nodes.

Secondary objectives :

* To compare toxicity and quality of life between the 2 above-mentioned arms.
* To evaluate pathologic and molecular markers for predicting efficacy.


Eligibility criteria: Inclusion Criteria :

* Histologically proven breast cancer. Interval between definitive surgery that includes axillary lymph node dissection and registration is less than or equal to 60 days. A central pathology review may be performed post randomization for confirmation of diagnosis and molecular studies.
* Definitive surgical treatment must be either mastectomy, or breast conserving surgery with axillary lymph node dissection 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 Ductal Carcinoma In Situ (DCIS). Lobular carcinoma in-situ does not count as a positive margin.
* Histologic examination of the tumor: Invasive adenocarcinoma with at least one axillary lymph node (pN1) showing evidence of tumor among a minimum of six resected lymph nodes.
* Tumor must show negative HER2 neu proto-oncogene overexpression by FISH (Fluorescence In Situ Hybridization). Confirmation of non overexpression will be centrally assessed by authorized BCIRG (Breast Cancer International Research Group) laboratories prior to randomization.
* Estrogen and/or progesterone receptor analysis performed on the primary tumor prior to randomization. Results must be known at the time of randomization.(Note: Patients whose tumor is estrogen receptor negative with progesterone receptor status unknown or undetermined, must have the progesterone receptor assayed in order to determine hormonal receptor status. Patients whose tumor is progesterone receptor negative with estrogen receptor status unknown or undetermined, must have the estrogen receptor assayed in order to determine hormonal receptor status).
* Karnofsky Performance status index \> 80%.
* Normal cardiac function must be confirmed by LVEF (Lef Ventricular Ejection Fraction) i.e. MUGA (Multi Gated Acquisition) scan or echocardiography and ECG within 3 months prior to registration. LVEF result must be above or equal to the lower limit of normal for the institution. The ECG results must be within normal limits or show no significant abnormalities.
* Laboratory requirements: (within 14 days prior to registration)

  * Hematology:

    * Neutrophils \> or = 2.0 x 10\^9/L
    * Platelets \> or = 100 x 10\^9/L
    * Hemoglobin \> or = 10 g/dL
  * Hepatic function:

    * Total bilirubin \< or = 1 UNL (Upper Normal Limit)
    * ASAT (Aspartate Amino Transferase) and ALAT (Alanine Amino Transferase) \< or = 2.5 UNL
    * Alkaline phosphatase \< or = 5 UNL
    * Patients with ASAT and/or ALAT \> 1.5 x UNL associated with alkaline phosphatase \> 2.5 x UNL are not eligible for the study.
  * Renal function:

    * Creatinine \< or = 175 µmol/L (2 mg/dL);
    * If limit reached, the calculated creatinine clearance should be \> or = 60mL/min.
* Complete staging work-up within 3 months prior to registration. All patients will have contralateral mammography, chest X-ray (Posteroanterior and lateral) and/or CT scan and/or MRI (Magnetic Resonance Imaging), abdominal ultrasound and/or CT scan (computerized tomography) and/or MRI, and bone scan. In case of positive bone scan, bone X-ray is mandatory to rule out the possibility of non-metastatic hot spots. 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.

Exclusion Criteria :

* Prior systemic anticancer therapy for breast cancer (immunotherapy, hormonotherapy, genetherapy , chemotherapy).
* Prior anthracycline therapy or taxoids (paclitaxel, docetaxel) for any malignancy.
* 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-CTC (National Cancer Institute - Common Toxicity Criteria), version 2.0.
* Other serious illness or medical condition:

  * congestive heart failure or unstable angina pectoris, previous history of myocardial infarction within 1 year from study entry, uncontrolled hypertension or high-risk uncontrolled arrhythmias
  * history of significant neurologic or psychiatric disorders including psychotic disorders, dementia or seizures that would prohibit the understanding and giving of informed consent
  * active uncontrolled infection
  * active peptic ulcer, unstable diabetes mellitus
* Past or current history of neoplasm other than breast carcinoma, except for:

  * curatively treated non-melanoma skin cancer
  * carcinoma in situ of the cervix
  * other cancer curatively treated and with no evidence of disease for at least 10 years
  * ipsilateral ductal carcinoma in-situ (DCIS) of the breast
  * lobular carcinoma in-situ (LCIS) of the breast
* 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 should be stopped before study entry.
* 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.
* 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.

The above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.

Primary outcomes:
measure: Local, Regional or Metastatic Relapse, or Second Primary Cancer, or Death From Any Cause (Disease-Free Survival)
timeFrame: Median follow-up 65 months
Secondary outcomes:
measure: Death From Any Cause (Overall Survival)
timeFrame: Median follow-up of 65 months
Other outcomes:
Locations:
city: Bridgewater
country: United States
facility: Sanofi-Aventis
state: New Jersey
city: Buenos Aires
country: Argentina
facility: Sanofi-Aventis
city: Macquarie Park
country: Australia
facility: Sanofi-Aventis
city: Brussels
country: Belgium
facility: Sanofi-Aventis
city: Sarajevo
country: Bosnia and Herzegovina
facility: Sanofi-Aventis
city: Sao Paulo
country: Brazil
facility: Sanofi-Aventis
city: Sofia
country: Bulgaria
facility: Sanofi-Aventis
city: Laval
country: Canada
facility: Sanofi-Aventis
city: Shanghai
country: China
facility: Sanofi-Aventis
city: Bogota
country: Colombia
facility: Sanofi-Aventis
city: Zagreb
country: Croatia
facility: Sanofi-Aventis
city: Nikosia
country: Cyprus
facility: Sanofi-Aventis
city: Praha
country: Czech Republic
facility: Sanofi-Aventis
city: Cairo
country: Egypt
facility: Sanofi-Aventis
city: Tallin
country: Estonia
facility: Sanofi-Aventis
city: Paris
country: France
facility: Sanofi-Aventis
city: Berlin
country: Germany
facility: Sanofi-Aventis
city: Kallithea
country: Greece
facility: Sanofi-Aventis
city: Hong Kong
country: Hong Kong
facility: Sanofi-Aventis
city: Budapest
country: Hungary
facility: Sanofi-Aventis
city: Dublin
country: Ireland
facility: Sanofi-Aventis
city: Natanya
country: Israel
facility: Sanofi-Aventis
city: Seoul
country: Korea, Republic of
facility: Sanofi-Aventis
city: Beirut
country: Lebanon
facility: Sanofi-Aventis
city: Mexico
country: Mexico
facility: Sanofi-Aventis
city: Auckland
country: New Zealand
facility: Sanofi-aventis
city: Warsaw
country: Poland
facility: Sanofi-Aventis
city: Porto Salvo
country: Portugal
facility: Sanofi-Aventis
city: Bucuresti
country: Romania
facility: Sanofi-Aventis
city: Moscow
country: Russian Federation
facility: Sanofi-Aventis
city: Jeddah
country: Saudi Arabia
facility: Sanofi-Aventis
city: Ljubljana
country: Slovenia
facility: Sanofi-Aventis
city: Midrand
country: South Africa
facility: Sanofi-Aventis
city: Barcelona
country: Spain
facility: Sanofi-Aventis
city: Taipei
country: Taiwan
facility: Sanofi-Aventis
city: Montevideo
country: Uruguay
facility: Sanofi-Aventis
city: Caracas
country: Venezuela
facility: Sanofi-Aventis
Study officials:
affiliation: Sanofi
name: Jean-Philippe AUSSEL
role: STUDY_DIRECTOR
References:
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.
citation: Mackey JR, Pienkowski T, Crown J, Sadeghi S, Martin M, Chan A, Saleh M, Sehdev S, Provencher L, Semiglazov V, Press MF, Sauter G, Lindsay M, Houe V, Buyse M, Drevot P, Hitier S, Bensfia S, Eiermann W. Long-term outcomes after adjuvant treatment of sequential versus combination docetaxel with doxorubicin and cyclophosphamide in node-positive breast cancer: BCIRG-005 randomized trial. Ann Oncol. 2016 Jun;27(6):1041-1047. doi: 10.1093/annonc/mdw098. Epub 2016 Mar 2.