Docetaxel, Carboplatin, Trastuzumab, and Pertuzumab With or Without Estrogen Deprivation in Treating Patients With Hormone Receptor-Positive, HER2-Positive Operable or Locally Advanced Breast Cancer

PRIMARY OBJECTIVES:

I. To determine whether the addition of estrogen deprivation to neoadjuvant therapy
consisting of therapy of docetaxel, carboplatin, trastuzumab, and pertuzumab (TCHP) yields a
greater rate of pathologic complete response (pCR) (breast and nodes) than TCHP alone when
administered to women with operable, hormone receptor-positive, HER2-positive breast cancer.

SECONDARY OBJECTIVES:

I. To determine whether the addition of estrogen deprivation to neoadjuvant therapy
consisting of TCHP will increase the pCR rate in the breast compared to TCHP alone when
administered to women with operable, hormone receptor-positive, HER2-positive breast cancer.

II. To determine whether the addition of estrogen deprivation to neoadjuvant therapy
consisting of TCHP improves recurrence-free interval (RFI) in women with operable, hormone
receptor-positive, HER2-positive breast cancer.

III. To determine whether the addition of estrogen deprivation to neoadjuvant therapy
consisting of TCHP improves overall survival (OS) in women with operable, hormone
receptor-positive, HER2-positive breast cancer.

IV. To compare the rates of second primary invasive cancer by treatment arm. V. Assessment of
patterns of pCR, RFI, and OS by menopausal status. VI. To evaluate the cardiac toxicity
associated with each of the regimens. VII. To compare the effect of adding estrogen
deprivation to neoadjuvant therapy on endocrine-related symptoms in all patients by treatment
arm.

VIII. To compare the effect of adding estrogen deprivation to neoadjuvant therapy on
vasomotor symptoms, musculoskeletal, and vaginal complaints as well as quality of life.

IX. To determine a relationship between pCR and a potential mechanism of
resistance/sensitivity in hormone receptor-positive, HER2-positive tumors.

X. To evaluate tumor infiltrating lymphocytes (TILs) and immune biomarkers as predictors of
pCR.

XI. To study early changes in TILs and other immune biomarkers in response to TCHP.

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

NEOADJUVANT:

ARM I: Patients receive docetaxel intravenously (IV) over 60 minutes, carboplatin IV over
30-60 minutes, trastuzumab IV over 30-90 minutes, and pertuzumab IV over 30-60 on day 1.
Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or
unacceptable toxicity. Patients enrolled after Amendment #4 undergo 2 core biopsies prior to
course 3 of treatment.

ARM II: All patients receive docetaxel, carboplatin, trastuzumab, and pertuzumab as in arm I.
Premenopausal patients also receive goserelin acetate subcutaneously (SC) every 28 days until
surgery and aromatase inhibition therapy at the investigator's discretion daily until 1 day
before surgery. Postmenopausal patients receive aromatase inhibition therapy at the
investigator's discretion daily until 1 day before surgery. Patients enrolled after Amendment
#4 undergo 2 core biopsies prior to course 3 of treatment.

SURGERY: Patients undergo lumpectomy or mastectomy.

RADIATION: Patients undergo whole breast irradiation within 8 weeks following surgery.

ADJUVANT: Patients receive trastuzumab IV over 30-60 minutes every 21 days for up to 1 year.

After completion of study treatment, patients are followed up every 6, 9, 12, and 18 months
for 5 years.

Inclusion Criteria:

- Patients should have a life expectancy of at least 10 years, excluding their diagnosis
of breast cancer; (comorbid conditions should be taken into consideration, but not the
diagnosis of breast cancer)

- Women of reproductive potential must agree to use an effective non-hormonal method of
contraception during study therapy (chemotherapy, trastuzumab, pertuzumab, and
estrogen deprivation therapy) and for at least 7 months after the last dose of study
therapy

- Submission of tumor samples is required for all patients; the local pathology
department policy regarding release of tumor samples must be considered in the
screening process; patients whose tumor samples are located in a pathology department
that by policy will not submit any samples for research purposes should not be
approached for participation in the B-52 trial

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

- The patient must have an Eastern Cooperative Oncology Group (ECOG) performance status
of 0 or 1

- Clinical staging for the primary tumor can be cT1c (must be 2.0 cm) or T2-T4 if
clinically node negative; if the regional lymph nodes are cN1 and cytologically or
histologically positive or if cN2-N3 with or without a biopsy, the primary breast
tumor can be cT0-T4

- The diagnosis of invasive adenocarcinoma of the breast must have been made by core
needle biopsy

- Ipsilateral axillary lymph nodes must be evaluated by imaging (mammogram, ultrasound,
and/or magnetic resonance imaging [MRI]) within 6 weeks prior to randomization; if
suspicious or abnormal, fine needle aspirate (FNA) or core biopsy is recommended, also
within 6 weeks prior to randomization; findings of these evaluations will be used to
determine the nodal status prior to randomization:

- Nodal status - negative

- Imaging of the axilla is negative

- Imaging is suspicious or abnormal but the FNA or core biopsy of the
questionable node(s) on imaging is negative

- Nodal status - positive

- FNA or core biopsy of the node(s) is cytologically or histologically
suspicious or positive

- Imaging is suspicious or abnormal but FNA or core biopsy was not performed

- Patients may be premenopausal or postmenopausal at the time of randomization; for
study purposes, postmenopausal is defined as:

- Age 56 or older with no spontaneous menses for at least 12 months prior to study
entry; or

- Age 55 or younger with no spontaneous menses for at least 12 months prior to
study entry (e.g., spontaneous or secondary to hysterectomy) and with a
documented estradiol level in the postmenopausal range according to local
institutional/laboratory standard; or

- Documented bilateral oophorectomy

- The tumor must have been determined to be HER2-postive as follows:

- Immunohistochemistry (IHC) 3+ or

- In situ hybridization (ISH)-positive (defined by ratio of HER2 to circulating
endothelial progenitors [CEP]17 >= 2.0 or HER2 gene copy number >= 6 per nucleus)

- The tumor must have been determined to be estrogen receptor (ER) and/or progesterone
(PgR) positive assessed by current American Society of Clinical Oncology
(ASCO)/College of American Pathologist (CAP) guideline recommendations for hormone
receptor testing; patients with >= 1% ER or PgR staining by IHC are considered
positive

- 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 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

- Alkaline phosphatase and AST may not both be > the ULN; for example, if the alkaline
phosphatase is > the ULN but =< 2.5 x ULN, the AST must be =< the ULN; if the AST is >
the ULN but =< 1.5 x ULN, the alkaline phosphatase must be =< ULN; 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], MRI, positron emission tomography
[PET]-CT, or PET scan) performed within 6 weeks prior to randomization does not
demonstrate metastatic disease and the requirements 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 6 weeks prior to randomization does not demonstrate metastatic
disease

- Within 6 weeks prior to randomization, the most recent serum creatinine must be =< ULN
or measured or calculated creatinine clearance must be > 60 mL/min

- Left ventricular ejection fraction (LVEF) assessment must be performed within 90 days
prior to randomization; (LVEF assessment performed by 2-dimensional [2-D]
echocardiogram is preferred; however, multi gated acquisition scan [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; note: since the pre-entry LVEF
serves as the baseline for comparing subsequent LVEF assessments, it is critical that
this baseline study be an accurate assessment; if the baseline LVEF is > 65%, the
investigator is encouraged to have the accuracy of the initial LVEF result confirmed
and repeat the test if the accuracy is uncertain

Exclusion Criteria:

- FNA alone to diagnose the breast cancer

- Excisional biopsy or lumpectomy performed prior to randomization

- Surgical axillary staging procedure prior to randomization; pre-neoadjuvant therapy
sentinel node biopsy is not permitted

- 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 bilateral invasive breast cancer

- Synchronous or previous contralateral invasive breast cancer; (patients with
synchronous and/or previous contralateral ductal carcinoma in situ [DCIS] or lobular
carcinoma in situ [LCIS] are eligible)

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

- Treatment including radiation therapy (RT), chemotherapy, targeted therapy, or
endocrine therapy for the currently diagnosed breast cancer prior to randomization

- Previous endocrine therapy such as raloxifene or tamoxifen (or other selective
estrogen receptor modulator [SERM]) or an aromatase inhibitor for any malignancy

- Previous therapy with anthracycline, taxanes, carboplatin, trastuzumab, or other HER2
targeted therapies for any malignancy

- Any sex hormonal therapy, e.g., birth control pills, ovarian hormone replacement
therapy, etc. (these patients are eligible if this therapy is discontinued prior to
randomization)

- 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

- 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; and

- Symptomatic pericarditis

- History of cardiac disease:

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

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

- 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

- Intrinsic lung disease resulting in dyspnea

- Poorly controlled diabetes mellitus

- Active infection or chronic infection requiring chronic suppressive antibiotics

- 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; patients taking
anti-retroviral therapy that may have a potential overlapping toxicity with the study
therapy are not eligible

- Nervous system disorder (paresthesia, peripheral motor neuropathy, or peripheral
sensory neuropathy) >= grade 2, per the Common Terminology Criteria for Adverse Events
version 4.0 (CTCAE v4.0)

- Malabsorption syndrome, ulcerative colitis, resection of the stomach or small bowel,
or other disease significantly affecting gastrointestinal function

- Other non-malignant systemic disease that would preclude treatment with any of the
treatment regimens or would prevent required follow-up

- 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 any of the ingredients or
excipients of these drugs (e.g., polysorbate 80), including sensitivity to benzyl
alcohol

- 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)

- 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