Breast Cancer
Conditions
Keywords
Breast Cancer, Adjuvant, Doxorubicin, Cyclophosphamide, Paclitaxel, Ixabepilone, TITAN
Brief summary
This is a randomized, Phase III, open-label, multicenter study.
Detailed description
Patients will be randomized in a 1:1 ratio to receive one of two different treatment arms. Patients in treatment arm 1 will receive AC followed by ixabepilone. Patients in treatment arm 2 will receive AC followed by weekly paclitaxel.
Interventions
DRUGDoxorubicin
Doxorubicin 60 mg/m2
DRUGCyclophosphamide
Cyclophosphamide 600 mg/m2
DRUGIxabepilone (Ixempra)
Ixabepilone 40 mg/m2
Paclitaxel 80 mg/m2
Sponsors
Bristol-Myers Squibb
SCRI Development Innovations, LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Female patients greater than or equal to18 years of age. 2. Histologically confirmed invasive unilateral breast cancer (regardless of histology). 3. Early-stage breast cancer, defined as: * Node-positive disease: \>0.2-mm metastasis in at least one lymph node (pN1mipN2b)OR * Node-negative, with primary tumor \>1.0 cm (T1c-T3). 4. Definitive loco-regional surgery must have been completed as specified below: * Patients must have undergone either breast conservation surgery (i.e., lumpectomy) or total mastectomy. * Surgical margins of the resected section must be histologically free of invasive adenocarcinoma and ductal carcinoma in situ. * Surgical margins involved with lobular carcinoma in situ (LCIS) will not be considered as a positive margin; therefore, such patients will be eligible for this study without additional resection. * Patients must have completed axillary lymph node sampling for the pathologic evaluation of axillary lymph nodes as specified below: Sentinel node biopsy and/or either lymph node sampling procedure or axillary dissection. 5. Multicentric and multifocal invasive breast cancer is eligible if loco-regional surgery has been completed as described above. 6. Patients with synchronous bilateral cancers are eligible only if: * All cancers are of triple-negative phenotype, defined as ER-, PR-, HER2-. * Eligibility based on the highest stage grouping. 7. HER2 negative tumors. HER2 negativity must be confirmed by one of the following: * FISH-negative (FISH ratio \<2.2), or * IHC 0-1+, or * IHC 2-3+ AND FISH-negative (FISH ratio \<2.2). 8. Estrogen receptor negative (\<10% staining by IHC for estrogen receptor). 9. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1. 10. Patient must be \<= 84 days from having completed definitive primary breast surgery (either lumpectomy or mastectomy). 11. MammoSite brachytherapy radiation is acceptable if it is performed immediately following surgery and prior to chemotherapy. It is recommended that chemotherapy be started no earlier than 2 weeks following the removal of the MammoSite balloon catheter. 12. Adequate hematologic function, defined by: * Absolute neutrophil count (ANC) \>1500/mm3 * Platelet count \>=100,000/mm3 * Hemoglobin \>9 g/dL 13. Adequate liver function, defined by: * AST and ALT \<=2.5 x the upper limit of normal (ULN) * Total bilirubin \<=1.5 x ULN (unless the patient has grade 1 bilirubin elevation due to Gilbert's disease or a similar syndrome involving slow conjugation of bilirubin). 14. Adequate renal function, defined by: * Serum creatinine \<=1.5 x ULN 15. Complete staging work-up \<=12 weeks prior to initiation of study treatment with computed tomography (CT) scans of the chest and abdomen/pelvis (abdomen/pelvis preferred; abdomen accepted), and either a positron emission tomography (PET) scan or a bone scan. 16. Adequate cardiac function, defined by a left ventricular ejection fraction (LVEF) value of \>50% (or normal per institutional guidelines) by MUGA scan or echocardiogram (ECHO). 17. Adequate recovery from recent surgery. At least 1 week must have elapsed from the time of a minor surgery (i.e., sentinel node biopsy, port-acath (placement); at least 3 weeks must have elapsed from the time of a major surgery (i.e., lumpectomy, partial or total mastectomy, axillary lymph node dissection, breast reconstruction procedure). 18. Patients with previous history of invasive cancers (including breast cancer) are eligible if definitive treatment was completed more than 5 years prior to initiating current study treatment, and there is no evidence of recurrent disease. 19. Women of childbearing potential must have a negative serum or urine pregnancy test performed within 7 days prior to start of treatment. If a woman becomes pregnant or suspects she is pregnant while participating in this study, she must agree to inform her treating physician immediately. 20. Patient must be accessible for treatment and follow-up. 21. Women of childbearing potential must agree to use an acceptable method of birth control to avoid pregnancy for the duration of study treatment, and for 3 months thereafter. 22. All patients must be able to understand the investigational nature of the study and give written informed consent prior to study entry.
Exclusion criteria
1. Women who are pregnant or breastfeeding. 2. History of previous diagnosis of invasive breast cancer (unless treated \>5 years previously with no recurrence). History of previously treated ductal carcinoma in situ (DCIS) is acceptable. 3. Any evidence or suspicion of metastatic disease other than ipsilateral axillary lymph nodes. 4. Any tumor \>=T4 (cutaneous invasion, deep adherence, inflammatory breast cancer). 5. Previous anthracycline chemotherapy. 6. Concurrent use of CYP3A4 inhibitors from 72 hours prior to initiation of study treatment until the end of treatment with ixabepilone. 7. Previous treatment for this breast cancer (including neoadjuvant chemotherapy). 8. Previous cancer (with the exception of non-melanoma skin cancer or cervical carcinoma in situ) in the past 5 years (including invasive contralateral breast cancer). 9. Peripheral neuropathy of \> grade 1 per NCI CTCAE v3.0. 10. Cardiac disease, including: congestive heart failure (CHF) \> Class II per New York Heart Association (NYHA) classification; unstable angina (anginal symptoms at rest) or new-onset angina (i.e., began within the last 3 months), or myocardial infarction within the past 6 months; symptomatic CHF, unstable angina pectoris, cardiac arrhythmia, or cardiac ventricular arrhythmias requiring anti-arrhythmic therapy. 11. History of hypersensitivity to CremophorEL (polyoxyethylated castor oil) or a drug formulated in CremophorEL such as paclitaxel. 12. Use of any investigational agent within 30 days of administration of the first dose of study drug. 13. Patients may not receive any other investigational or anti-cancer treatments while participating in this study. 14. Concurrent severe, uncontrolled infection or intercurrent illness including, but not limited to, ongoing or active infection, or psychiatric illness/social situations that would limit compliance with study requirements. 15. Mental condition that would prevent patient comprehension of the nature of, and risk associated with, the study. 16. Inability to comply with study and/or follow-up procedures.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Disease-free Survival | up to 5.25 years (63 months) | The percentage of participants with disease-free survival at 3 and 5 years. Disease-free survival (DFS) is measured from the time between randomization and the date of first documented disease recurrence, or death from any cause. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | up to 5.25 years (63 months) | The percentage of participants with overall survival at 3 and 5 years are presented. Overall survival (OS) defined as the time between randomization to date of death from any cause. |
Countries
Puerto Rico, United States
Participant flow
Recruitment details
The trial was designed to evaluate if doxorubicin+cyclophosphamide (AC) followed by ixabepilone was more effective than AC followed by standard weekly paclitaxel as adjuvant treatment for patients with operable triple negative breast cancer (TNBC). Between Dec 2008 and Jan 2011, 614 women with early-stage TNBC were enrolled from 63 U.S. sites.
Pre-assignment details
Subjects were randomized in a 1:1 ratio to either of 2 arms: 306 to AC/Ixabepilone (Ixa); 308 to AC/paclitaxel (Pac). 489 patients completed all planned treatment with AC/Ixa or AC/Pac.
Participants by arm
| Arm | Count |
|---|---|
| Ixabepilone Doxorubicin and cyclophosphamide (AC) given every 3 weeks for 4 cycles, followed by ixabepilone every 3 weeks for 4 cycles.
Doxorubicin: 60 mg/m2
Cyclophosphamide: 600 mg/m2
Ixabepilone (Ixempra): 40 mg/m2 | 306 |
| Paclitaxel Doxorubicin and cyclophosphamide (AC) given every 3 weeks for 4 cycles, followed by paclitaxel weekly for 12 weeks.
Doxorubicin: 60 mg/m2
Cyclophosphamide: 600 mg/m2
Paclitaxel (Taxol): 80 mg/m2 | 308 |
| Total | 614 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| AC Therapy | Adverse Event | 2 | 3 |
| AC Therapy | Disease recurrence | 3 | 1 |
| AC Therapy | Intercurrent Illness | 1 | 0 |
| AC Therapy | Never Treated | 1 | 4 |
| AC Therapy | Other | 0 | 2 |
| AC Therapy | Withdrawal by Subject | 4 | 7 |
| Adjuvant Therapy | Adverse Event | 20 | 44 |
| Adjuvant Therapy | Disease recurrence | 2 | 1 |
| Adjuvant Therapy | Intercurrent Illness | 1 | 3 |
| Adjuvant Therapy | Never treated | 2 | 2 |
| Adjuvant Therapy | Other | 0 | 1 |
| Adjuvant Therapy | Protocol Violation | 1 | 1 |
| Adjuvant Therapy | Withdrawal by Subject | 14 | 5 |
Baseline characteristics
| Characteristic | Ixabepilone | Paclitaxel | Total |
|---|---|---|---|
| Age, Customized <50 years | 124 Participants | 93 Participants | 217 Participants |
| Age, Customized ≥50 years | 182 Participants | 215 Participants | 397 Participants |
| Menopausal Status Postmenopausal | 206 Participants | 224 Participants | 430 Participants |
| Menopausal Status Premenopausal | 100 Participants | 84 Participants | 184 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 2 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Asian | 3 Participants | 1 Participants | 4 Participants |
| Race (NIH/OMB) Black or African American | 61 Participants | 52 Participants | 113 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 3 Participants | 4 Participants | 7 Participants |
| Race (NIH/OMB) White | 237 Participants | 251 Participants | 488 Participants |
| Sex: Female, Male Female | 306 Participants | 308 Participants | 614 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 | 305 / 305 | 304 / 304 |
| serious Total, serious adverse events | 58 / 305 | 50 / 304 |
Outcome results
Primary
Disease-free Survival
The percentage of participants with disease-free survival at 3 and 5 years. Disease-free survival (DFS) is measured from the time between randomization and the date of first documented disease recurrence, or death from any cause.
Time frame: up to 5.25 years (63 months)
Population: The intent-to-treat population (all randomized patients) are included in the analysis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ixabepilone | Disease-free Survival | 3-year DFS | 88.6 percentage of participants |
| Ixabepilone | Disease-free Survival | 5-year DFS | 87.1 percentage of participants |
| Paclitaxel | Disease-free Survival | 3-year DFS | 88.8 percentage of participants |
| Paclitaxel | Disease-free Survival | 5-year DFS | 84.7 percentage of participants |
Secondary
Overall Survival
The percentage of participants with overall survival at 3 and 5 years are presented. Overall survival (OS) defined as the time between randomization to date of death from any cause.
Time frame: up to 5.25 years (63 months)
Population: The intent-to-treat population (all randomized patients) are included in the analysis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ixabepilone | Overall Survival | 3-year OS | 92.4 percentage of participants |
| Ixabepilone | Overall Survival | 5-year OS | 89.7 percentage of participants |
| Paclitaxel | Overall Survival | 3-year OS | 93.8 percentage of participants |
| Paclitaxel | Overall Survival | 5-year OS | 89.6 percentage of participants |