Doxorubicin Hydrochloride and Cyclophosphamide Followed by Paclitaxel With or Without Carboplatin in Treating Patients With Triple-Negative Breast Cancer

PRIMARY OBJECTIVES:

I. To determine whether the addition of carboplatin to an adjuvant chemotherapy regimen of
doxorubicin (doxorubicin hydrochloride)/cyclophosphamide followed by paclitaxel will improve
the invasive disease-free survival (IDFS) compared to doxorubicin/cyclophosphamide followed
by paclitaxel when administered to patients with operable node-positive or high-risk
node-negative triple-negative breast cancer.

SECONDARY OBJECTIVES:

I. To determine whether the addition of carboplatin to an adjuvant chemotherapy regimen of
doxorubicin/cyclophosphamide followed by paclitaxel will improve the overall survival (OS)
compared to doxorubicin/cyclophosphamide followed by paclitaxel when administered to
patients with operable node-positive or high-risk node-negative triple-negative breast
cancer.

II. To determine whether the addition of carboplatin to an adjuvant chemotherapy regimen of
doxorubicin/cyclophosphamide followed by paclitaxel will improve the breast cancer-free
survival (BCFS) compared to doxorubicin/cyclophosphamide followed by paclitaxel when
administered to patients with operable node-positive or high-risk node-negative
triple-negative breast cancer.

III. To determine whether the addition of carboplatin to an adjuvant chemotherapy regimen of
doxorubicin/cyclophosphamide followed by paclitaxel will improve the recurrence-free
interval (RFI) compared to doxorubicin/cyclophosphamide followed by paclitaxel when
administered to patients with operable node-positive or high-risk node-negative
triple-negative breast cancer.

IV. To determine whether the addition of carboplatin to an adjuvant chemotherapy regimen of
doxorubicin/cyclophosphamide followed by paclitaxel will improve the distant recurrence-free
interval (DRFI) compared to doxorubicin/cyclophosphamide followed by paclitaxel when
administered to patients with operable node-positive or high-risk node-negative
triple-negative breast cancer.

V. To determine the toxicity of doxorubicin/cyclophosphamide followed by paclitaxel
administered concurrently with carboplatin compared to the toxicity of
doxorubicin/cyclophosphamide followed by paclitaxel alone.

VI. To determine if germline breast cancer (BRCA) status is associated with benefit in IDFS
or OS from the addition of carboplatin to an adjuvant chemotherapy regimen of
doxorubicin/cyclophosphamide followed by paclitaxel in patients with operable node-positive
or high-risk node-negative triple-negative breast cancer.

VII. To determine if the addition of carboplatin will improve the RFI among the homologous
recombination (HR) deficient patients as determined by the homologous recombination
deficiency (HRD) score.

VIII. To determine whether the efficacy of carboplatin on RFI in HR-deficient patients
differs from that in patients who are not HR-deficient.

IX. To collect tissue and blood samples at several occasions for future biomarkers
development in predicting risk of breast cancer recurrence in patients with operable
node-positive or high-risk node-negative triple-negative breast cancer treated with
doxorubicin/cyclophosphamide followed by paclitaxel with or without carboplatin and
predicting benefit from the addition of carboplatin among these patients.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I (DOXORUBICIN HYDROCHLORIDE [A] CYCLOPHOSPHAMIDE [C]-->WEEKLY PACLITAXEL [WP]):
Patients receive doxorubicin hydrochloride intravenously (IV) over 15 minutes and
cyclophosphamide IV over 30 minutes on day 1. Treatment repeats every 2 weeks for 4 courses
in the absence of disease progression or unacceptable toxicity. Patients then receive
paclitaxel IV over 60 minutes on day 1. Treatment repeats weekly for 12 courses in the
absence of disease progression or unacceptable toxicity.

ARM II (AC-->WP + CARBOPLATIN): Patients receive doxorubicin hydrochloride and
cyclophosphamide as in Arm I. Patients then receive paclitaxel IV over 60 minutes on days 1,
8, and 15 and carboplatin IV over 30-60 minutes on day 1. Treatment repeats every 3 weeks
for 4 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 6 months for 5 years and
then every 12 months for 5 years.

Inclusion Criteria:

- The patient must have signed and dated an institutional review board (IRB)-approved
consent form that conforms to federal and institutional guidelines

- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

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

- All of the following staging criteria (according to the 7th edition of the American
Joint Committee on Cancer [AJCC] Cancer Staging Manual) must be met:

- By pathologic evaluation, primary tumor must be pT1-3

- By pathologic evaluation, ipsilateral nodes must be pN0, pN1 (pN1mi, pN1a, pN1b,
pN1c), pN2a, pN2b, pN3a, or pN3b

- If pN0, tumor must be > 3.0 cm

- The tumor must have been determined to be human epidermal growth factor receptor 2
(HER2)-negative as follows:

- Immunohistochemistry (IHC) 0-1+; or

- IHC 2+ and in situ hybridization (ISH) non-amplified with a ratio of HER2 to
centromere enumerator probe 17 (CEP17) < 2.0, and if reported, average HER2 gene
copy number < 4 signals/cells; or

- ISH non-amplified with a ratio of HER2 to CEP17 < 2.0, and if reported, average
HER2 gene copy number < 4 signals/cells

- The tumor must have been determined to be estrogen receptor (ER)-and progesterone
receptor (PgR)-negative assessed by current American Society of Clinical Oncology
(ASCO)/College of American Pathologists (CAP) guidelines; patients with < 1% ER and
PgR staining by IHC are considered negative

- The patient must have undergone either a mastectomy (total, skin-sparing, or
nipple-sparing) or 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 excisions may be performed to obtain clear margins;
if tumor is still present at the resected margin after re-excision(s), the patient
must undergo mastectomy to be eligible; (patients with margins positive for lobular
carcinoma in situ [LCIS] are eligible without additional resection)

- For patients who undergo mastectomy, the margins must be free of residual gross
tumor; (patients with microscopic positive margins are eligible as long as
post-mastectomy radiation therapy [RT] of the chest wall will be administered)

- The patient must have completed one of the procedures for evaluation of pathologic
nodal status listed below.

- Sentinel lymphadenectomy alone:

- If pathologic nodal staging based on sentinel lymphadenectomy is pN0 or
pN1b;

- If pathologic nodal staging based on sentinel lymphadenectomy is pN1mi or
pN1a and the patient has undergone breast conserving surgery (with planned
breast radiotherapy), the primary tumor must be T1 or T2 by pathologic
evaluation and the nodal involvement must be limited to 1 or 2 positive
nodes

- 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 (including re-excision of
margins) and randomization must be no more than 60 days

- Absolute neutrophil count (ANC) must be >= 1200/mm^3

- Platelet count must be >= 100,000/mm^3

- Hemoglobin must be >= 10 g/dL

- Total bilirubin must be =< upper limit of normal (ULN) for the laboratory (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

- Alkaline phosphatase must be =< 2.5 x ULN for the lab

- Aspartate aminotransferase (AST) must be =< 1.5 x ULN for the lab

- Note: If alanine aminotransferase (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 (computed tomography [CT], magnetic resonance imaging [MRI],
positron emission tomography [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 or unexplained bone
pain 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

- Adequate renal function determined within 6 weeks prior to randomization defined as
the most recent serum creatinine =< ULN or measured or calculated creatinine
clearance > 60 mL/min

- Left ventricular ejection fraction (LVEF) assessment must be performed within 90 days
prior to randomization; (LVEF assessment performed by 2-dimensional [D]
echocardiogram is preferred; however, multi gated acquisition [MUGA] scan may be
substituted based on institutional preferences;) the LVEF must be >= 50% regardless
of the cardiac imaging facility's lower limit of normal

Exclusion Criteria:

- T4 tumors including inflammatory breast cancer

- Definitive clinical or radiologic evidence of metastatic disease; required imaging
studies 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 or LCIS are eligible)

- Any previous history of ipsilateral invasive breast cancer or ipsilateral DCIS;
(patients with synchronous or previous ipsilateral LCIS are eligible)

- History of non-breast malignancies (except for in situ cancers treated only by local
excision and basal cell and squamous cell carcinomas of the skin) within 5 years
prior to randomization

- Previous therapy with anthracyclines or taxanes for any malignancy

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

- Any continued use of sex hormonal therapy, e.g., birth control pills, ovarian hormone
replacement therapy; patients are eligible if these medications are discontinued
prior to randomization

- 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 current 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; or

- Symptomatic pericarditis

- History of cardiac disease

- Myocardial infarction documented by elevated cardiac enzymes or persistent
regional wall abnormalities on assessment of left ventricle (LV) function;

- History of documented congestive heart failure (CHF); or

- Documented cardiomyopathy

- Uncontrolled hypertension defined as sustained systolic blood pressure (BP) > 150
mmHg or diastolic BP > 90 mmHg; (patients with initial BP elevations are eligible if
initiation or adjustment of BP medication lowers pressure to meet entry criteria)

- Active hepatitis B or hepatitis C with abnormal liver function tests

- Patients known to be human immunodeficiency virus (HIV) positive with a baseline
cluster of differentiation (CD)4 count of < 250 cells/mm^3 or have a history of
acquired immune deficiency syndrome (AIDS) indicator conditions

- Intrinsic lung disease resulting in dyspnea

- History of hospitalization in past 12 months for diabetic ketoacidosis (DKA) or
hyperosmolar hyperglycemic nonketotic syndrome (HHNS)

- Active infection or chronic infection requiring chronic suppressive antibiotics

- Nervous system disorder (paresthesia, peripheral motor neuropathy, or peripheral
sensory neuropathy) >= grade 2, per the Common Terminology Criteria for Adverse
Events (CTCAE) version (v)4.0

- Conditions that would prohibit administration of corticosteroids

- Chronic daily treatment with corticosteroids with a dose of >= 10 mg/day
methylprednisolone equivalent (excluding inhaled steroids)

- Known hypersensitivity to any of the study drugs or excipients, e.g., polysorbate 80
and Cremophor® EL

- 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

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

- Use of any investigational product within 4 weeks prior to randomization