Breast Cancer
Conditions
Brief summary
The purpose of this research study is to find out what effects (good and bad) TC or TAC has on early stage HER2- breast cancer.
Detailed description
Both TAC (docetaxel, doxorubicin, and cyclophosphamide) and TC (docetaxel and cyclophosphamide) are established adjuvant chemotherapy regimens for early stage breast cancer. TAC, however, due to the inclusion of the anthracycline doxorubicin, carries a high risk of hematologic and cardiotoxic adverse effects. Substantial evidence supports the concept that early stage HER2-negative breast cancers will benefit similarly from anthracycline-based adjuvant and non-anthracycline-based chemotherapy. Further, approximately 0 to 9% of HER2-negative breast cancers have alterations in the TOP2A gene, which may predict for benefit from anthracycline-based chemotherapy. We hypothesize that 6 cycles of TC versus 6 cycles of TAC will have similar efficacy in the treatment of early stage HER2-negative breast cancer and that TC will have less toxicity. If this hypothesis were upheld and the anthracycline doxorubicin could be eliminated from the regimen while obtaining similar efficacy in this population of patients, it would not only be an important advance in the understanding of the biology of cancer, but it would also be of significant clinical benefit to women with breast cancer.
Interventions
DRUGDocetaxel
Docetaxel 75 mg/m2 IV over 1 hour on Day 1 followed by cyclophosphamide
DRUGDoxorubicin
• Doxorubicin 50 mg/m2 IV push over 5-15 minutes via sidearm through a running IV line on Day 1, followed by cyclophosphamide 500 mg/m2 IV over 15-30 minutes on Day 1, followed by docetaxel 75 mg/m2 IV over 1 hour on Day 1. Administer pegfilgrastim 6 mg SC on Day 2 (or filgrastim 5 mcg/kg SC per standard of care).
DRUGCyclophosphamide
600 mg/m2 IV over 15-30 minutes on Day 1.
Sponsors
Sanofi
US Oncology Research
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
A woman will be eligible for inclusion in this study if she meets all of the following criteria: * Age \>18 to \<70 years old. * Has known ER and PR status * Has HER2 nonamplified disease, confirmed by FISH * Has known menopausal status (see Section 7.3 for criteria) * Has operable, histologically confirmed, Stage I, IIA, IIB, or IIIA, IIIB, or IIIC invasive carcinoma of the breast. Bilateral synchronous breast cancer is allowable provided that 1 primary meets the inclusion criteria. * Meets 1 of the 3 following criteria: * T1-3N1-3M0 if ER positive or negative * T2-3N0M0 if ER positive or negative * T1N0M0 if ER and PR negative * Has complete surgical resection of the primary breast tumor: either lumpectomy or mastectomy with sentinel lymph node biopsy or axillary dissection, with clear margins for both invasive and ductal carcinoma in situ (DCIS) * Has had no prior chemotherapy unless \>5 years ago * Has an ECOG Performance Status (PS) 0-1 * Has laboratory values of: See protocol for specific details * Has aspartate aminotransferase (AST) or alanine aminotransferase (ALT) and alkaline phosphatase (ALP) within the ranges shown below. In determining eligibility the more abnormal of the 2 values (AST or ALT) should be used. See protocol for specific details * Has normal cardiac function as evidenced by a LVEF \>50%, but WNL by institutional standard by multiple gated acquisition (MUGA) scan. An echocardiogram (ECHO) may be used if MUGA is not available, but the same modality must be used consistently throughout the study to evaluate LVEF. Ejection fraction as determined by ECHO must be WNL by institutional standard. * Has no evidence of metastatic disease outside of breast by physical examination and chest x-ray. Other scans if done as needed by the patient (eg, bone scan; abdominal, chest CT; PET or PET/CT; ultrasound; or MRI should indicate no evidence of metastatic disease * Has had baseline bilateral mammography * It has been \<84 days since the date of definitive surgery (eg, mastectomy or, in the case of a breast-sparing procedure, axillary dissection) with adequate wound healing, as determined by the Treating Physician * Has a negative serum pregnancy test within 7 calendar days prior to registration (female patients of childbearing potential \[not surgically sterilized and between menarche and 1 year postmenopause\]) * If fertile, patient has agreed to use an acceptable method of birth control (barrier contraceptive only) to avoid pregnancy for the duration of the study and for a period of 3 months thereafter * Has adequate tumor specimen available for FISH analysis of TOP2A status (See Appendix VI). * Has signed a Patient Informed Consent Form * Has signed a Patient Authorization Form
Exclusion criteria
A woman will be excluded from this study if she meets any of the following criteria: * Has any evidence of metastatic disease following surgical resection of the primary tumor including: positive surgical margins, staging work-up, or physical examination suspicious for malignant disease * Has T4 disease (ie, patients with fixed tumors, peau d'orange skin changes, skin ulcerations, or inflammatory changes) * Has Stage IV breast cancer (M1 disease on TNM staging system) * Has a history of severe hypersensitivity reaction to drugs formulated with polysorbate 80 * Has had neoadjuvant chemotherapy for this breast cancer * Has ever had a myocardial infarction (MI) or has a history of heart failure, uncontrolled angina, severe uncontrolled arrhythmias, pericardial disease, or electrocardiographic evidence of acute ischemic changes * Is receiving concurrent immunotherapy, hormonal therapy (eg, tamoxifen, hormone replacement therapy), or radiation therapy. Must discontinue prior to registering on the study. * Is receiving concurrent investigational therapy or has received such therapy within the past 30 calendar days * Has peripheral neuropathy \>Grade 1 * Has had a major organ allograft or condition requiring chronic immunosuppression (ie, kidney, liver, lung, heart, bone marrow transplant, or autoimmune diseases). Patients who have received corneal transplants or cadaver skin or bone transplants are eligible. * Has a serious uncontrolled intercurrent medical or psychiatric illness, including serious viral (including clinically defined AIDS), bacterial or fungal infection; or history of uncontrolled seizures, or diabetes, or CNS disorders deemed by the Treating Physician to be clinically significant, precluding informed consent * Has active hepatitis B or hepatitis C with abnormal liver function tests (LFTs) or is known to be HIV positive * Has a history of other malignancy within the last 5 years (except cured basal cell carcinoma of skin, carcinoma in situ of uterine cervix, DCIS, which could affect the diagnosis or assessment of any of the study drugs * In an obese patient to whom the Treating Physician would not be comfortable administering full doses of study drugs as calculated by the BSA. Obese patients will be treated based on actual body weight. Obese patients treated with full doses based on actual BSA are eligible. * Is pregnant or breastfeeding * Is deemed unable to comply with requirements of study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 3-year Invasive Disease-free Survival (IDFS) Among Analyzed ITT Patients | 3 years from randomization into study | The primary objective of the study is to compare the 3-year invasive disease-free survival (IDFS) of adjuvant TC versus TAC as treatment for early stage HER2-negative breast cancer among analyzed ITT patients. ITT patients are all patients who were randomized, whether or not they followed protocol. IDFS, defined as the time from the date of randomization to local recurrence following mastectomy, invasive local recurrence in the ipsilateral breast following lumpectomy, regional recurrence, distant recurrence, invasive contralateral breast cancer, second primary cancer (other than squamous or basal cell carcinoma of the skin, melanoma in situ, carcinoma in situ of the cervix, colorectal carcinoma in situ, or lobular carcinoma in situ of the breast), or death from any cause prior to recurrence or second primary cancer. Patients who have not had any such event at the time of data analysis will be censored at the last date they were known to be event-free. |
| 3-year Invasive Disease-free Survival (IDFS) Among Per-protocol Patients | 3 years from randomization into study | The primary objective of the study is to compare the 3-year invasive disease-free survival (IDFS) of adjuvant TC versus TAC as treatment for early stage HER2-negative breast cancer among per-protocol patients. Per-protocol only includes those patients who were randomized and received treatment as outlined in the protocol. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number and Frequency of Participants by TOP2A Status by Study Treatment | 10 years (from baseline to end of study participation) | To evaluate the effectiveness of TC and TAC in TOP2A altered (amplified, deleted, or overexpressed at the protein level) early stage HER2-negative breast cancer |
| 3-year DFS-DCIS, OS and RFI Among Analyzed ITT Patients | 3 years from randomization into study | To compare disease-free survival-ductal carcinoma in situ (DFS-DCIS),overall survival (OS) and recurrence free interval (RFI) of TC with TAC. DFS-DCIS, defined as the time from the date of randomization to local recurrence following mastectomy, local recurrence in the ipsilateral breast following lumpectomy (invasive or non-invasive), regional recurrence, distant recurrence, contralateral breast cancer (invasive or non-invasive), second primary cancer (other than squamous or basal cell carcinoma of the skin, melanoma in situ, carcinoma in situ of the cervix, colorectal carcinoma in situ, or lobular carcinoma in situ of the breast), or death from any cause prior to recurrence or second primary cancer. Patients who have not had any such event at the time of data analysis will be censored at the last date they were known to be event-free. |
| 3-year DFS Stratified by TOP2A Among TAC Arm | 3 years from randomization into study | To evaluate DFS among TAC in TOP2A altered (amplified, deleted, or overexpressed at the protein level) early stage HER2-negative breast cancer. |
| 3-year DFS Stratified by TOP2A Among TC Arm | 3 years from randomization into study | To evaluate DFS among TC in TOP2A altered (amplified, deleted, or overexpressed at the protein level) early stage HER2-negative breast cancer. |
| 3-year DFS-DCIS, OS and RFI Among Per-protocol Patients. | 3 years from randomization into study | To compare disease-free survival-ductal carcinoma in situ (DFS-DCIS),overall survival (OS) and recurrence free interval (RFI) of TC with TAC among per protocol patients. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| TC Arm docetaxel 75 mg/m2 and cyclophosphamide 600 mg/m2
Docetaxel: Docetaxel 75 mg/m2 IV over 1 hour on Day 1 plus Cyclophosphamide 600 mg/m2 IV over 15-30 minutes on Day 1 Q 21 day cycles X 6. | 969 |
| TAC Arm doxorubicin 50 mg/m2, cyclophosphamide 500 mg/m2 and docetaxel 75 mg/m2
Docetaxel: Docetaxel 75 mg/m2 IV over 1 hour on Day 1 followed by cyclophosphamide
Doxorubicin: • Doxorubicin 50 mg/m2 IV push over 5-15 minutes via sidearm through a running IV line on Day 1, plus cyclophosphamide 500 mg/m2 IV over 15-30 minutes on Day 1, plus docetaxel 75 mg/m2 IV over 1 hour on Day 1, followed by pegfilgrastim 6 mg SC (or filgrastim 5 mcg/kg SC) on Day 2 Q 21 day cycles X 6. | 965 |
| Total | 1,934 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 12 | 15 |
Baseline characteristics
| Characteristic | Total | TC Arm | TAC Arm |
|---|---|---|---|
| Age, Continuous | 53.3 years STANDARD_DEVIATION 9.1 | 53.4 years STANDARD_DEVIATION 9.2 | 53.1 years STANDARD_DEVIATION 8.9 |
| Baseline Performance Status (ECOG) ECOG 0 | 1717 Participants | 860 Participants | 857 Participants |
| Baseline Performance Status (ECOG) ECOG 1 | 217 Participants | 109 Participants | 108 Participants |
| Grade Moderately/Intermediate | 747 Participants | 370 Participants | 377 Participants |
| Grade Poorly/Undifferentiated | 901 Participants | 470 Participants | 431 Participants |
| Grade Unknown | 67 Participants | 29 Participants | 38 Participants |
| Grade Well/Low | 219 Participants | 100 Participants | 119 Participants |
| Histology Ductal | 1600 Participants | 811 Participants | 789 Participants |
| Histology Lobular | 187 Participants | 87 Participants | 100 Participants |
| Histology Mixed | 50 Participants | 24 Participants | 26 Participants |
| Histology Other | 95 Participants | 47 Participants | 48 Participants |
| Histology Unknown | 2 Participants | 0 Participants | 2 Participants |
| Hormone Receptor Status Negative | 577 Participants | 290 Participants | 287 Participants |
| Hormone Receptor Status Positive | 1357 Participants | 679 Participants | 678 Participants |
| Menopausal Status Peri | 83 Participants | 41 Participants | 42 Participants |
| Menopausal Status Post | 1181 Participants | 602 Participants | 579 Participants |
| Menopausal Status Pre | 667 Participants | 324 Participants | 343 Participants |
| Menopausal Status Unknown | 3 Participants | 2 Participants | 1 Participants |
| Positive Nodes 0 nodes | 697 Participants | 358 Participants | 339 Participants |
| Positive Nodes 10+ nodes | 75 Participants | 40 Participants | 35 Participants |
| Positive Nodes 1-3 nodes | 935 Participants | 455 Participants | 480 Participants |
| Positive Nodes 4-9 nodes | 227 Participants | 116 Participants | 111 Participants |
| Race/Ethnicity, Customized Asian | 33 Participants | 11 Participants | 22 Participants |
| Race/Ethnicity, Customized Black | 189 Participants | 94 Participants | 95 Participants |
| Race/Ethnicity, Customized Caucasian | 1459 Participants | 718 Participants | 741 Participants |
| Race/Ethnicity, Customized Hawaiian | 2 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized Hispanic | 238 Participants | 141 Participants | 97 Participants |
| Race/Ethnicity, Customized Indian | 3 Participants | 1 Participants | 2 Participants |
| Race/Ethnicity, Customized Other | 7 Participants | 2 Participants | 5 Participants |
| Race/Ethnicity, Customized Unknown | 3 Participants | 2 Participants | 1 Participants |
| Sex: Female, Male Female | 1934 Participants | 969 Participants | 965 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
| Stage I | 260 Participants | 136 Participants | 124 Participants |
| Stage II | 1421 Participants | 705 Participants | 716 Participants |
| Stage III | 253 Participants | 128 Participants | 125 Participants |
| Tumor size | 2.6 cm STANDARD_DEVIATION 1.5 | 2.7 cm STANDARD_DEVIATION 1.5 | 2.6 cm STANDARD_DEVIATION 1.5 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 110 / 969 | 88 / 965 |
| other Total, other adverse events | 680 / 969 | 746 / 965 |
| serious Total, serious adverse events | 264 / 969 | 330 / 965 |
Outcome results
Primary
3-year Invasive Disease-free Survival (IDFS) Among Analyzed ITT Patients
The primary objective of the study is to compare the 3-year invasive disease-free survival (IDFS) of adjuvant TC versus TAC as treatment for early stage HER2-negative breast cancer among analyzed ITT patients. ITT patients are all patients who were randomized, whether or not they followed protocol. IDFS, defined as the time from the date of randomization to local recurrence following mastectomy, invasive local recurrence in the ipsilateral breast following lumpectomy, regional recurrence, distant recurrence, invasive contralateral breast cancer, second primary cancer (other than squamous or basal cell carcinoma of the skin, melanoma in situ, carcinoma in situ of the cervix, colorectal carcinoma in situ, or lobular carcinoma in situ of the breast), or death from any cause prior to recurrence or second primary cancer. Patients who have not had any such event at the time of data analysis will be censored at the last date they were known to be event-free.
Time frame: 3 years from randomization into study
Population: Analyzed ITT population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| TC Arm | 3-year Invasive Disease-free Survival (IDFS) Among Analyzed ITT Patients | 91.1 percentage of participants |
| TAC Arm | 3-year Invasive Disease-free Survival (IDFS) Among Analyzed ITT Patients | 93.2 percentage of participants |
p-value: 0.05Log Rank
Primary
3-year Invasive Disease-free Survival (IDFS) Among Per-protocol Patients
The primary objective of the study is to compare the 3-year invasive disease-free survival (IDFS) of adjuvant TC versus TAC as treatment for early stage HER2-negative breast cancer among per-protocol patients. Per-protocol only includes those patients who were randomized and received treatment as outlined in the protocol.
Time frame: 3 years from randomization into study
Population: Per-protocol patients
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| TC Arm | 3-year Invasive Disease-free Survival (IDFS) Among Per-protocol Patients | 91.3 percentage of participants |
| TAC Arm | 3-year Invasive Disease-free Survival (IDFS) Among Per-protocol Patients | 93.2 percentage of participants |
Secondary
3-year DFS-DCIS, OS and RFI Among Analyzed ITT Patients
To compare disease-free survival-ductal carcinoma in situ (DFS-DCIS),overall survival (OS) and recurrence free interval (RFI) of TC with TAC. DFS-DCIS, defined as the time from the date of randomization to local recurrence following mastectomy, local recurrence in the ipsilateral breast following lumpectomy (invasive or non-invasive), regional recurrence, distant recurrence, contralateral breast cancer (invasive or non-invasive), second primary cancer (other than squamous or basal cell carcinoma of the skin, melanoma in situ, carcinoma in situ of the cervix, colorectal carcinoma in situ, or lobular carcinoma in situ of the breast), or death from any cause prior to recurrence or second primary cancer. Patients who have not had any such event at the time of data analysis will be censored at the last date they were known to be event-free.
Time frame: 3 years from randomization into study
Population: Analyzed ITT population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| TC Arm | 3-year DFS-DCIS, OS and RFI Among Analyzed ITT Patients | 3-year DFS-DCIS | 90.9 percentage of participants |
| TC Arm | 3-year DFS-DCIS, OS and RFI Among Analyzed ITT Patients | 3-year OS | 96.8 percentage of participants |
| TC Arm | 3-year DFS-DCIS, OS and RFI Among Analyzed ITT Patients | 3-year RFI | 91.9 percentage of participants |
| TAC Arm | 3-year DFS-DCIS, OS and RFI Among Analyzed ITT Patients | 3-year DFS-DCIS | 93.0 percentage of participants |
| TAC Arm | 3-year DFS-DCIS, OS and RFI Among Analyzed ITT Patients | 3-year OS | 96.8 percentage of participants |
| TAC Arm | 3-year DFS-DCIS, OS and RFI Among Analyzed ITT Patients | 3-year RFI | 94.5 percentage of participants |
Secondary
3-year DFS-DCIS, OS and RFI Among Per-protocol Patients.
To compare disease-free survival-ductal carcinoma in situ (DFS-DCIS),overall survival (OS) and recurrence free interval (RFI) of TC with TAC among per protocol patients.
Time frame: 3 years from randomization into study
Population: Analyzed per-protocol patients
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| TC Arm | 3-year DFS-DCIS, OS and RFI Among Per-protocol Patients. | 3-year DFS-DCIS | 91.1 percentage of participants |
| TC Arm | 3-year DFS-DCIS, OS and RFI Among Per-protocol Patients. | 3-year OS | 96.8 percentage of participants |
| TC Arm | 3-year DFS-DCIS, OS and RFI Among Per-protocol Patients. | 3-year RFI | 92.1 percentage of participants |
| TAC Arm | 3-year DFS-DCIS, OS and RFI Among Per-protocol Patients. | 3-year DFS-DCIS | 93.0 percentage of participants |
| TAC Arm | 3-year DFS-DCIS, OS and RFI Among Per-protocol Patients. | 3-year OS | 96.8 percentage of participants |
| TAC Arm | 3-year DFS-DCIS, OS and RFI Among Per-protocol Patients. | 3-year RFI | 94.5 percentage of participants |
Secondary
3-year DFS Stratified by TOP2A Among TAC Arm
To evaluate DFS among TAC in TOP2A altered (amplified, deleted, or overexpressed at the protein level) early stage HER2-negative breast cancer.
Time frame: 3 years from randomization into study
Population: Analyzed ITT patients with TOP2A data among TAC arm.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| TC Arm | 3-year DFS Stratified by TOP2A Among TAC Arm | 100 percentage of participants |
| TAC Arm | 3-year DFS Stratified by TOP2A Among TAC Arm | 90.9 percentage of participants |
| Normal | 3-year DFS Stratified by TOP2A Among TAC Arm | 93.2 percentage of participants |
Secondary
3-year DFS Stratified by TOP2A Among TC Arm
To evaluate DFS among TC in TOP2A altered (amplified, deleted, or overexpressed at the protein level) early stage HER2-negative breast cancer.
Time frame: 3 years from randomization into study
Population: Analyzed ITT patients with TOP2A data
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| TC Arm | 3-year DFS Stratified by TOP2A Among TC Arm | 85.1 percentage of participants |
| TAC Arm | 3-year DFS Stratified by TOP2A Among TC Arm | 82.8 percentage of participants |
| Normal | 3-year DFS Stratified by TOP2A Among TC Arm | 93.8 percentage of participants |
Secondary
Number and Frequency of Participants by TOP2A Status by Study Treatment
To evaluate the effectiveness of TC and TAC in TOP2A altered (amplified, deleted, or overexpressed at the protein level) early stage HER2-negative breast cancer
Time frame: 10 years (from baseline to end of study participation)
Population: Analyzed ITT patients with TOP2A data
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| TC Arm | Number and Frequency of Participants by TOP2A Status by Study Treatment | Amplification | 14 Participants |
| TC Arm | Number and Frequency of Participants by TOP2A Status by Study Treatment | Deletion | 131 Participants |
| TC Arm | Number and Frequency of Participants by TOP2A Status by Study Treatment | Normal | 479 Participants |
| TAC Arm | Number and Frequency of Participants by TOP2A Status by Study Treatment | Amplification | 14 Participants |
| TAC Arm | Number and Frequency of Participants by TOP2A Status by Study Treatment | Deletion | 128 Participants |
| TAC Arm | Number and Frequency of Participants by TOP2A Status by Study Treatment | Normal | 489 Participants |