NSABP B-49 I: A Phase III Clinical Trial Comparing the Combination of Docetaxel Plus Cyclophosphamide to Anthracycline-Based Chemotherapy Regimens for Women with Node-Positive or High-Risk Node-Negative, HER2-Negative Breast Cancer
The B-49 study, a multicenter, open-label, randomized Phase III, adjuvant therapy trial, will compare the value of a non-anthracycline-based chemotherapy regimen relative to anthracycline-based chemotherapy regimens in women with resected node-positive or high-risk node-negative, HER2-negative breast cancer. This trial will compare invasive disease-free survival of a regimen of docetaxel and cyclophosphamide (TC) to anthracycline-based chemotherapy regimens. Secondary aims will evaluate the regimens in terms of disease-free survival, overall survival, and recurrence-free interval. The toxicities of the regimens will also be compared.
Patients in the B-49 study will be randomized to one of two treatment regimens: Arm 1 patients will receive 1 of 4 anthracycline-based chemotherapy regimens per investigator choice; Arm 2 patients will receive 6 cycles of TC administered every 21 days (docetaxel 75 mg/m2, cyclophosphamide 600 mg/m2). Primary prophylaxis with growth factor support is required for Arm 1 Regimens A, C, and D patients (optional for patients in Arm 1 Regimen B and Arm 2). Patients will also receive adjuvant radiation therapy as clinically indicated and endocrine therapy for hormone receptor-positive tumors.
Chemotherapy for Arm 1 regimen A(TAC):
Doxorubicin (A)-50 mg/m2 via sidearm through a running IV over 5-15 minutes (Day 1 every 3 weeks; Cycles 1-6)
Cyclophosphamide (C)-500 mg/m2 IV over 15-30 minutes(Day 1 every 3 weeks: Cycles 1-6)
Docetaxel (T)-75 mg/m2 IV over 60 minutes(Day 1 every 3 weeks; Cycles 1-6)
Chemotherapy for Arm 1 regimen B (AC[?]WP):
Doxorubicin (A)-60 mg/m2 IV over 15 minutes(Day 1 every 3 weeks; Cycles 1-4)
Cyclophosphamide (C)-600 mg/m2 IV over 30 minutes(Day 1 every 3 weeks; Cycles 1-4)
Initiate 3 weeks after the last dose of AC
Paclitaxel (WP)-80 mg/m2 IV over 60 minutes(Weekly; 12 doses)
Chemotherapy for Arm 1 regimen C (DD AC[?]WP):
Doxorubicin (A)-60 mg/m2 IV over 15 minutes (Day 1 every 2 weeks: Cycles 1x4)
Cyclophosphamide (C)-600 mg/m2 IV over 30 minutes(Day 1 every 2 weeks: Cycles 1x4)
Initiate 2-3 weeks after the last dose of AC
Paclitaxel (WP)-80 mg/m2 IV over 60 minutes (Weekly; 12 doses)
Chemotherapy for Arm 1 regimen D (DD AC[?] DD P):
Doxorubicin (A)-60 mg/m2 IV over 15 minutes(Day 1 every 2 weeks; Cycles 1x4)
Cyclophosphamide (C)-600 mg/m2 IV over 30 minutes(Day 1 every 2 weeks; Cycles 1x4)
Initiate 2-3 weeks after the last dose of AC
Paclitaxel (P)-175 mg/m2 IV over 3 hours (Day 1 every 2 weeks; Cycles 5x8)
Chemotherapy for Arm 2 (TC):
Docetaxel (T)-75 mg/m2 IV over 60 minutes (Day 1 every 3 weeks; Cycles 1-6)
Cyclophosphamide (C)-600 mg/m2 IV over 15-30 minutes(Day 1 every 3 weeks; Cycles 1-6)
The patient or, if applicable, her legally authorized representative must have signed and dated an IRB-approved consent form that conforms to federal and institutional guidelines.
4.2.2 Patients must be female.
4.2.3 The patient must be >= 18 years old.
4.2.4 The patient must have an ECOG performance status of 0 or 1 (see Appendix A).
4.2.5 The tumor must be unilateral invasive adenocarcinoma of the breast on histologic examination.
4.2.6 The breast cancer must be HER2-negative based on current ASCO/CAP Guideline Recommendations for Human Epidermal Growth Factor Receptor 2 Testing in Breast Cancer. If the result of the in situ hybridization testing (FISH, CISH, or other) is equivocal, the patient is eligible if there is no plan to administer HER2-targeted therapy.
4.2.7 All of the following staging criteria must be met according to AJCC criteria:
* By pathologic evaluation, primary tumor must be pT1-3;
* By pathologic evaluation, ipsilateral nodes must be pN0, pN1 (pN1mi, pN1a, pN1b, pN1c), pN2a, pN3a, or pN3b.
If pN0, at least one of the following criteria must be met:
[?] ER negative and PgR negative; or
[?] Pathologic tumor size > 2.0 cm; or
[?] T1c (pathologic tumor size > 1.0 cm but <= 2.0 cm) and ER positive (PgR status may be positive or negative) and either grade 3 histology or Oncotype DX(RegisteredTM) Recurrence Score of >= 25.
4.2.8 Patients must have undergone either a total mastectomy or breast-conserving surgery (lumpectomy).
4.2.9 For patients who undergo lumpectomy, the margins of the resected specimen must be histologically free of invasive tumor and DCIS as determined by the local pathologist. If pathologic examination demonstrates tumor at the line of resection, additional operative procedures must be performed to obtain clear margins. If tumor is still present at the resected margin after re-excision(s), the patient must undergo total mastectomy to be eligible. (Patients with margins positive for lobular carcinoma in situ [LCIS] are eligible without additional resection.)
4.2.10 For patients who undergo mastectomy, margins must be histologically free of invasive tumor and DCIS.
4.2.11 Patients must have completed one of the following procedures for evaluation of pathologic nodal status:
* Sentinel lymphadenectomy alone if pathologic nodal staging based on sentinel lymphadenectomy is pN0, pN1mi, or pN1b;
* Sentinel lymphadenectomy alone if pathologic nodal staging based on sentinel lymphadenectomy is pN1a limited to 1 or 2 positive nodes and primary tumor is T1 or T2 by pathologic evaluation;
* Sentinel lymphadenectomy followed by removal of additional non-sentinel lymph nodes if the sentinel node (SN) is positive; or
* Axillary lymphadenectomy with or without SN isolation procedure.
4.2.12 The interval between the last surgery for breast cancer (treatment or staging) and randomization must be no more than 84 days.
4.2.13 Patients must have ER analysis performed on the primary tumor prior to randomization. Breast cancer must be assessed for ER status by current ASCO/CAP Guideline Recommendations for hormone receptor testing. If negative for ER, assessment of PgR must also be performed according to current ASCO/CAP Guideline Recommendations for hormone receptor testing. (Either a core biopsy or surgical resection specimen can be used for ER/PgR testing.)
4.2.14 The most recent postoperative blood counts, performed within 6 weeks prior to randomization, must meet the following criteria:
* ANC must be >= 1200/mm3;
* platelet count must be >= 100,000/mm3
* hemoglobin must be >= 10 g/dL.
4.2.15 The following criteria for evidence of adequate hepatic function must be met based on the results of the most recent postoperative tests performed within 6 weeks prior to randomization:
* total bilirubin must be <= ULN for the lab unless the patient has a bilirubin elevation > ULN to 1.5 x ULN due to Gilbert[Single Quote]s disease or similar syndrome involving slow conjugation of bilirubin
* alkaline phosphatase must be <= 2.5 x ULN for the lab
* AST must be <= 1.5 x ULN for the lab.
* Alkaline phosphatase and AST may not both be > the ULN. For example, if the alkaline phosphatase is > the ULN but <= 2.5 x ULN, then the AST must be <= the ULN. If the AST is > the ULN but <= 1.5 x ULN, then the alkaline phosphatase must be <= ULN.
Note: If ALT is performed instead of AST (per institution's standard practice), the ALT value must be <= 1.5 x ULN; if both were performed, the AST must be <= 1.5 x ULN.
4.2.16 Patients with AST or alkaline phosphatase > ULN are eligible for inclusion in the study if liver imaging (CT, MRI, PET-CT, or PET scan performed within 90 days prior to randomization) does not demonstrate metastatic disease and the requirements in criterion 4.2.15 are met.
4.2.17 Patients with alkaline phosphatase that is > ULN but <= 2.5 x ULN are eligible for inclusion in the study if a bone scan, PET-CT scan, or PET scan performed within 90 days prior to randomization does not demonstrate metastatic disease.
4.2.18 The most recent postoperative serum creatinine performed within 6 weeks prior to randomization must be <= ULN for the lab.
4.2.19 LVEF assessment by 2-D echocardiogram or MUGA scan must be performed within 90 days prior to randomization. The LVEF must be >= 50% regardless of the facility[Single Quote]s LLN. (If the facility performing the assessment has not reported the LVEF as a whole number, decimals reported as >= 5 should be rounded up and decimals reported as < 5 should be rounded down.)