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CTSU NSABP B-49

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

Eligibility Criteria
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.

Patients must be female.

The patient must be ≥ 18 years old.

The patient must have an ECOG performance status of 0 or 1.

The tumor must be unilateral invasive adenocarcinoma of the breast on histologic examination.

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.

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® Recurrence Score of ≥ 25.

Patients must have undergone either a total mastectomy or breast-conserving surgery (lumpectomy).

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.)

For patients who undergo mastectomy, margins must be histologically free of invasive tumor and DCIS.

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.

The interval between the last surgery for breast cancer (treatment or staging) and randomization must be no more than 84 days.

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.)

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; and
• hemoglobin must be ≥ 10 g/dL.

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’s disease or similar syndrome involving slow conjugation of bilirubin; and
• alkaline phosphatase must be ≤ 2.5 x ULN for the lab; and
• 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.

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 above are met.

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.

The most recent postoperative serum creatinine performed within 6 weeks prior to randomization must be ≤ ULN for the lab.

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’s LLN. 

Ineligibility Criteria
Patients with one or more of the following conditions are ineligible for this study.

T4 tumors including inflammatory breast cancer.

Definitive clinical or radiologic evidence of metastatic disease.  (Chest imaging [mandatory for all patients] and other imaging [if required] must have been performed within 90 days prior to randomization.)

Synchronous or previous contralateral invasive breast cancer.  (Patients with synchronous
and/or previous contralateral DCIS are eligible.)

Any history of ipsilateral invasive breast cancer or ipsilateral DCIS.

History of non-breast malignancies within 5 years prior to randomization, except for the following: carcinoma in situ of the cervix, colorectal carcinoma in situ, melanoma in situ, and basal cell and squamous cell carcinomas of the skin.

Previous therapy with anthracyclines or taxanes for any malignancy.

Chemotherapy administered for the currently diagnosed breast cancer prior to randomization.

Continued endocrine therapy such as raloxifene or tamoxifen (or other SERM) or an aromatase inhibitor.  Patients are eligible if these medications are discontinued prior to randomization.

Any sex hormonal therapy, e.g., birth control pills, ovarian hormone replacement therapy.  Patients are eligible if these medications are discontinued prior to randomization.

Known active hepatitis B or hepatitis C with abnormal liver function tests.

Cardiac disease (history of and/or active disease) that would preclude the use of the drugs included in the treatment regimens.  This includes but is not confined to:
Active cardiac disease
• angina pectoris that requires the use of anti-anginal medication;
• ventricular arrhythmias except for benign premature ventricular contractions;
• supraventricular and nodal arrhythmias requiring a pacemaker or not controlled with medication;
• conduction abnormality requiring a pacemaker;
• valvular disease with documented compromise in cardiac function;
• symptomatic pericarditis.
History of cardiac disease
• myocardial infarction documented by elevated cardiac enzymes or persistent regional wall abnormalities on assessment of LV function;
• history of documented CHF;
• documented cardiomyopathy.

Whole breast RT prior to randomization or partial breast RT that cannot be completed on or before the date of randomization.

Intrinsic lung disease resulting in dyspnea.

Unstable diabetes mellitus.

Active infection or chronic infection requiring suppressive antibiotics.

History of a major organ allograft or condition requiring chronic immunosuppression, e.g., kidney, liver, lung, heart, bone marrow transplant, or autoimmune diseases.  (Patients who have received corneal transplants, cadaver skin, or bone transplants are eligible.)

Nervous system disorder (paresthesia, peripheral motor neuropathy, or peripheral sensory neuropathy) ≥ grade 2, per the CTCAE v4.0.

Conditions that would prohibit administration of corticosteroids.

Chronic daily treatment with corticosteroids (dose of ≥ 10 mg/day methylprednisolone equivalent, excluding inhaled steroids).

History of hypersensitivity reaction to drugs formulated with polysorbate 80.

Pregnancy or lactation at the time of study entry.  (Note: Pregnancy testing must be performed within 2 weeks prior to randomization according to institutional standards for women of childbearing potential.)

Other non-malignant systemic disease that would preclude the patient from receiving study treatment or would prevent required follow-up. Psychiatric or addictive disorders or other conditions that, in the opinion of the investigator, would preclude the patient from meeting the study requirements.

Use of any investigational product within 30 days prior to randomization.

Treatment Plan
Patients will be randomized to one of two arms.

Arm 1:  Patients will receive one of four approved anthracycline-based chemotherapy regimens
• TAC (docetaxel 75 mg/m2 IV + doxorubicin 50 mg/m2 IV + cyclophosphamide 500 mg/m2 IV q21 days x 6 cycles
• AC→WP (doxorubicin 60 mg/m2 IV + cyclophosphamide 600 mg/m2 IV q21 days x 4 cycles, followed by paclitaxel 80 mg/m2 weekly for 12 doses)
• DD AC→WP (doxorubicin 60 mg/m2 IV + cyclophosphamide 600 mg/m2 IV q14 days x 4 cycles, followed by paclitaxel 80 mg/m2 weekly for 12 doses)
• DD AC→DD P (doxorubicin 60 mg/m2 IV + cyclophosphamide 600 mg/m2 IV q14 days x 4 cycles, followed by paclitaxel 175 mg/m2 q14 days x 4 cycles)

Arm 2: Patients will receive docetaxel 75 mg/m2 IV + cyclophosphamide 600 m/m2 q21 days x 6 cycles

No medications are provided free of charge for this study.