Docetaxel and Cyclophosphamide Compared to Anthracycline-Based Chemotherapy in Treating Women With HER2-Negative Breast Cancer

OBJECTIVES:

Primary

- To determine if the docetaxel and cyclophosphamide (TC) regimen is non-inferior to the
anthracycline-based chemotherapy regimens in terms of invasive disease-free survival
(DFS) by combining B-49 data with the docetaxel, doxorubicin, and cyclophosphamide (TAC)
and TC arms of NSABP B-46-I/US Oncology Research, Inc.(USOR) 07132 and the data from
USOR 06-090.

Secondary

- To determine rates of DFS-ductal carcinoma in situ (DCIS) for the TC and
anthracycline-based chemotherapy regimens.

- To determine rates of overall survival (OS) for the TC and anthracycline-based
chemotherapy regimens.

- To determine rates of recurrence-free interval (RFI) for the TC and anthracycline-based
chemotherapy regimens.

- To evaluate the toxicity associated with each of the regimens.

- To determine the role of TOP2A in prognosis and prediction of degree of benefit from
anthracycline-based chemotherapy over TC. (exploratory)

- To develop predictive markers for benefit from doxorubicin. (exploratory)

OUTLINE: This is a multicenter randomized study. Patients are stratified according to number
of positive nodes (0 vs 1-3 vs 4-9 vs 10+) and hormone-receptor status (estrogen receptor
[ER] and/or progesterone receptor [PgR] positive vs ER and PgR negative). Patients are
randomized to 1 of 2 treatment arms.

Inclusion Criteria:

- The patient must have an Eastern Cooperative Oncology Group (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 Human Epidermal Growth Factor Receptor 2 (HER2)-negative
based on current American Society of Clinical Oncology (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, chromagen in situ
hybridization [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 American Joint
Committee on Cancer (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 greater than 2.0 cm; or

- T1c (pathologic tumor size greater than 1.0 cm but less than or equal to 2.0 cm)
and ER positive (PgR status may be positive or negative) and either grade 3
histology or Oncotype DX® Recurrence Score of greater than or equal to 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 ductal carcinoma in situ (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:

- absolute neutrophil count (ANC) must be greater than or equal to 1200/mm3;

- platelet count must be greater than or equal to 100,000/mm3; and

- hemoglobin must be greater than or equal to 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 less than or equal to upper limit of normal (ULN) for the
lab unless the patient has a bilirubin elevation greater than ULN to 1.5 x ULN
due to Gilbert's disease or similar syndrome involving slow conjugation of
bilirubin; and

- alkaline phosphatase must be less than or equal to 2.5 x ULN for the lab; and

- aspartate transaminase (AST) must be less than or equal to 1.5 x ULN for the lab.

- Alkaline phosphatase and AST may not both be greater than the ULN. For example,
if the alkaline phosphatase is greater than the ULN but less than or equal to 2.5
x ULN, then the AST must be less than or equal to the ULN. If the AST is greater
than the ULN but less than or equal to 1.5 x ULN, then the alkaline phosphatase
must be less than or equal to ULN.

- Note: If alanine aminotransferase (ALT) is performed instead of AST (per
institution's standard practice), the ALT value must be less than or equal to 1.5
x ULN; if both were performed, the AST must be less than or equal to 1.5 x ULN.

- Patients with AST or alkaline phosphatase greater than 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
for adequate hepatic function as described above are met.

- Patients with alkaline phosphatase that is greater than ULN but less than or equal to
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 less than or equal to ULN for the lab.

- Left ventricular ejection fraction (LVEF) assessment by 2-D echocardiogram or
multigated acquisition (MUGA) scan must be performed within 90 days prior to
randomization. The LVEF must be greater than or equal to 50% regardless of the
facility's lower limit of normal (LLN). (If the facility performing the assessment has
not reported the LVEF as a whole number, decimals reported as greater than or equal to
5 should be rounded up and decimals reported as less than 5 should be rounded down.)

Exclusion 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 left ventricular function;

- history of documented congestive heart failure (CHF);

- documented cardiomyopathy.

- Whole breast radiation therapy (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) greater than or equal to grade 2, per the NCI CTCAE v4.0.

- Conditions that would prohibit administration of corticosteroids.

- Chronic daily treatment with corticosteroids (dose of greater than or equal to 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.