Breast Cancer
Conditions
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.
Interventions
TAC x 6 : Docetaxel 75 mg/m² as 1 hour IV infusion on day 1 every 3 weeks in combination with doxorubicin 50 mg/m² as an IV bolus and cyclophosphamide 500 mg/m2 as IV on day 1 every 3 weeks. Sequence of administration is as follows: doxorubicin followed by cyclophosphamide followed by docetaxel.
DRUGDocetaxel,doxorubicin, cyclophosphamide
AC x 4: Doxorubicin 60 mg/m² as an IV bolus in combination with cyclophosphamide 600 mg/m² as IV followed by docetaxel 100 mg/m² as 1 hour IV infusion on day 1 every 3 weeks for 4 cycles.
Sponsors
Cancer International Research Group (CIRG)
Sanofi
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 70 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Local, Regional or Metastatic Relapse, or Second Primary Cancer, or Death From Any Cause (Disease-Free Survival) | Median follow-up 65 months | The primary event is the local, regional or metastatic relapse or the date of second primary cancer or death from any cause (whichever occurs first). The primary efficacy analysis is performed on the time from randomization to this primary event. The Measured Values table below presents the numbers of patients with the event at the end of the study period. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Death From Any Cause (Overall Survival) | Median follow-up of 65 months | The considered event is death from any cause. The analysis is performed on the time from randomization to this event. The Measured Values table below presents the numbers of patients with the event at the end of the study period. |
Countries
Argentina, Australia, Belgium, Bosnia and Herzegovina, Brazil, Bulgaria, Canada, China, Colombia, Croatia, Cyprus, Czechia, Egypt, Estonia, France, Germany, Greece, Hong Kong, Hungary, Ireland, Israel, Lebanon, Mexico, New Zealand, Poland, Portugal, Romania, Russia, Saudi Arabia, Slovenia, South Africa, South Korea, Spain, Taiwan, United States, Uruguay, Venezuela
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Doxorubicin + Cyclophosphamide Followed by Docetaxel (AC -> T) AC x 4: Doxorubicin 60 mg/m² as an IV bolus in combination with cyclophosphamide 600 mg/m² as IV followed by docetaxel 100 mg/m² as 1 hour IV infusion on day 1 every 3 weeks for 4 cycles. | 1,649 |
| Docetaxel + Doxorubicin and Cyclophosphamide (TAC) TAC x 6 : Docetaxel 75 mg/m² as 1 hour IV infusion on day 1 every 3 weeks in combination with doxorubicin 50 mg/m² as an IV bolus and cyclophosphamide 500 mg/m2 as IV on day 1 every 3 weeks. Sequence of administration is as follows: doxorubicin followed by cyclophosphamide followed by docetaxel. | 1,649 |
| Total | 3,298 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 97 | 61 |
| Overall Study | Death | 2 | 1 |
| Overall Study | Lack of Efficacy | 7 | 4 |
| Overall Study | Lost to Follow-up | 3 | 5 |
| Overall Study | Other | 5 | 7 |
| Overall Study | Protocol Violation | 5 | 3 |
| Overall Study | Withdrawal by Subject | 53 | 42 |
Baseline characteristics
| Characteristic | Docetaxel + Doxorubicin and Cyclophosphamide (TAC) | Doxorubicin + Cyclophosphamide Followed by Docetaxel (AC -> T) | Total |
|---|---|---|---|
| Age, Continuous | 50 years | 50 years | 50 years |
| Age, Customized < =35 years | 73 Participants | 91 Participants | 164 Participants |
| Age, Customized > =65 years | 83 Participants | 85 Participants | 168 Participants |
| Age, Customized Between 49 and 35 years | 710 Participants | 689 Participants | 1399 Participants |
| Age, Customized Between 65 and 50 years | 783 Participants | 784 Participants | 1567 Participants |
| Hormonal Receptor Status Negative | 303 Participants | 301 Participants | 604 Participants |
| Hormonal Receptor Status Positive | 1346 Participants | 1348 Participants | 2694 Participants |
| Karnofsky Performance Status at Baseline 100 - Normal no complaints; no evidence of disease | 1293 Participants | 1298 Participants | 2591 Participants |
| Karnofsky Performance Status at Baseline 80 - Activity with effort; some signs of disease | 33 Participants | 36 Participants | 69 Participants |
| Karnofsky Performance Status at Baseline 90 - Normal activity; minor signs of disease | 323 Participants | 315 Participants | 638 Participants |
| Menopausal status Post-Menopausal or Other age > 50 Years | 786 Participants | 783 Participants | 1569 Participants |
| Menopausal status Pre-Menopausal or Other age < 50 Years | 863 Participants | 866 Participants | 1729 Participants |
| Number of Positive Lymph Nodes [0] | 1 Participants | 0 Participants | 1 Participants |
| Number of Positive Lymph Nodes > 10 | 187 Participants | 177 Participants | 364 Participants |
| Number of Positive Lymph Nodes [1 to 3] | 1005 Participants | 1010 Participants | 2015 Participants |
| Number of Positive Lymph Nodes [4 to 10] | 456 Participants | 462 Participants | 918 Participants |
| Patients with at least one surgery Lumpectomy | 276 Participants | 283 Participants | 559 Participants |
| Patients with at least one surgery Mastectomy | 973 Participants | 955 Participants | 1928 Participants |
| Patients with at least one surgery Quadrantectomy/Segmental | 400 Participants | 411 Participants | 811 Participants |
| Primary Tumor pT1: Tumor < = 2cm | 668 Participants | 692 Participants | 1360 Participants |
| Primary Tumor pT2: Tumor in [ 2 - 5 ] | 844 Participants | 824 Participants | 1668 Participants |
| Primary Tumor pT3: Tumor > 5cm | 135 Participants | 131 Participants | 266 Participants |
| Primary Tumor pT4: Tumor with extension to chest wall/skin | 2 Participants | 1 Participants | 3 Participants |
| Primary Tumor pTis: Carcinoma in situ | 0 Participants | 1 Participants | 1 Participants |
| Region of Enrollment Argentina | 32 participants | 31 participants | 63 participants |
| Region of Enrollment Australia | 144 participants | 156 participants | 300 participants |
| Region of Enrollment Belgium | 31 participants | 33 participants | 64 participants |
| Region of Enrollment Bosnia And Herzegovina | 5 participants | 5 participants | 10 participants |
| Region of Enrollment Brazil | 21 participants | 19 participants | 40 participants |
| Region of Enrollment Bulgaria | 11 participants | 11 participants | 22 participants |
| Region of Enrollment Canada | 180 participants | 174 participants | 354 participants |
| Region of Enrollment China | 17 participants | 21 participants | 38 participants |
| Region of Enrollment Colombia | 8 participants | 6 participants | 14 participants |
| Region of Enrollment Croatia | 29 participants | 29 participants | 58 participants |
| Region of Enrollment Cyprus | 5 participants | 2 participants | 7 participants |
| Region of Enrollment Czech Republic | 10 participants | 11 participants | 21 participants |
| Region of Enrollment Egypt | 4 participants | 4 participants | 8 participants |
| Region of Enrollment Estonia | 2 participants | 3 participants | 5 participants |
| Region of Enrollment France | 58 participants | 59 participants | 117 participants |
| Region of Enrollment Germany | 223 participants | 224 participants | 447 participants |
| Region of Enrollment Greece | 3 participants | 5 participants | 8 participants |
| Region of Enrollment Hong Kong | 6 participants | 3 participants | 9 participants |
| Region of Enrollment Hungary | 35 participants | 34 participants | 69 participants |
| Region of Enrollment Ireland | 88 participants | 83 participants | 171 participants |
| Region of Enrollment Israel | 67 participants | 63 participants | 130 participants |
| Region of Enrollment Lebanon | 18 participants | 23 participants | 41 participants |
| Region of Enrollment Mexico | 3 participants | 5 participants | 8 participants |
| Region of Enrollment New Zealand | 19 participants | 21 participants | 40 participants |
| Region of Enrollment Poland | 168 participants | 167 participants | 335 participants |
| Region of Enrollment Portugal | 1 participants | 2 participants | 3 participants |
| Region of Enrollment Romania | 19 participants | 17 participants | 36 participants |
| Region of Enrollment Russian Federation | 35 participants | 32 participants | 67 participants |
| Region of Enrollment Saudi Arabia | 0 participants | 2 participants | 2 participants |
| Region of Enrollment Slovenia | 17 participants | 15 participants | 32 participants |
| Region of Enrollment South Africa | 21 participants | 19 participants | 40 participants |
| Region of Enrollment South Korea | 27 participants | 22 participants | 49 participants |
| Region of Enrollment Spain | 41 participants | 26 participants | 67 participants |
| Region of Enrollment Taiwan | 16 participants | 18 participants | 34 participants |
| Region of Enrollment United States | 278 participants | 294 participants | 572 participants |
| Region of Enrollment Uruguay | 2 participants | 4 participants | 6 participants |
| Region of Enrollment Venezuela | 5 participants | 6 participants | 11 participants |
| Sex: Female, Male Female | 1649 Participants | 1649 Participants | 3298 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 1,634 / 1,634 | 1,629 / 1,635 |
| serious Total, serious adverse events | 331 / 1,634 | 520 / 1,635 |
Outcome results
Primary
Local, Regional or Metastatic Relapse, or Second Primary Cancer, or Death From Any Cause (Disease-Free Survival)
The primary event is the local, regional or metastatic relapse or the date of second primary cancer or death from any cause (whichever occurs first). The primary efficacy analysis is performed on the time from randomization to this primary event. The Measured Values table below presents the numbers of patients with the event at the end of the study period.
Time frame: Median follow-up 65 months
Population: The primary efficacy analysis was performed on the Intent-to-Treat (ITT) population. Although the original Outcome Measure was intended to be presented as median disease free survival time, median time-to-event was not reached in any group; therefore, number of participants with relapse was presented.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Doxorubicin + Cyclophosphamide Followed by Docetaxel (AC -> T) | Local, Regional or Metastatic Relapse, or Second Primary Cancer, or Death From Any Cause (Disease-Free Survival) | 356 Participants |
| Docetaxel + Doxorubicin and Cyclophosphamide (TAC) | Local, Regional or Metastatic Relapse, or Second Primary Cancer, or Death From Any Cause (Disease-Free Survival) | 352 Participants |
p-value: 0.97895% CI: [0.86, 1.16]Log Rank
Secondary
Death From Any Cause (Overall Survival)
The considered event is death from any cause. The analysis is performed on the time from randomization to this event. The Measured Values table below presents the numbers of patients with the event at the end of the study period.
Time frame: Median follow-up of 65 months
Population: The analysis was performed on the Intent-to-Treat (ITT) population. Although the original Outcome Measure was intended to be presented as median survival time, median time-to-event was not reached in any group; therefore, number of participants who died was presented.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Doxorubicin + Cyclophosphamide Followed by Docetaxel (AC -> T) | Death From Any Cause (Overall Survival) | 187 Participants |
| Docetaxel + Doxorubicin and Cyclophosphamide (TAC) | Death From Any Cause (Overall Survival) | 202 Participants |
p-value: 0.37195% CI: [0.75, 1.11]Log Rank