Chemotherapy With or Without Trastuzumab After Surgery in Treating Women With Invasive Breast Cancer
Condition: HER2/Neu Positive; Progesterone Receptor Positive; Recurrent Breast Carcinoma; Stage IA Breast Cancer AJCC v7; Stage IB Breast Cancer AJCC v7; Stage IIA Breast Cancer AJCC v6 and v7; Stage IIB Breast Cancer AJCC v6 and v7; Stage IIIA Breast Cancer AJCC v7; Stage IIIC Breast Cancer AJCC v7
MeSH terms: Breast Neoplasms
Intervention: Cyclophosphamide; Docetaxel; Doxorubicin; Doxorubicin Hydrochloride; Laboratory Biomarker Analysis; Paclitaxel; Quality-of-Life Assessment; Trastuzumab
Intervention description: Given IV; Given IV; Given IV; Given IV; Correlative studies; Given IV; Ancillary studies; Given IV
Intervention MeSH terms: Paclitaxel; Docetaxel; Cyclophosphamide; Doxorubicin; Liposomal doxorubicin; Trastuzumab; Albumin-Bound Paclitaxel; Daunorubicin; Trastuzumab biosimilar HLX02
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 3270.0
Sex: Female
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      This randomized phase III clinical trial studies chemotherapy with or without trastuzumab
      after surgery to see how well they work in treating women with invasive breast cancer. Drugs
      used in chemotherapy work in different ways to stop the growth of tumor cells, either by
      killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving
      more than one drug (combination chemotherapy) and giving chemotherapy after surgery may kill
      more tumor cells. Monoclonal antibodies, such as trastuzumab, can block cancer growth in
      different ways. Some block the ability of tumor cells to grow and spread. Others find tumor
      cells and help kill them or carry tumor-killing substances to them. It is not yet known
      whether combination chemotherapy is more effective with trastuzumab in treating breast
      cancer.
    

Eligibility criteria:

        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 (for example condoms, some intrauterine devices, diaphragms, tubal
             ligation, vasectomized partner, or abstinence) during therapy and for at least 6
             months (Arm 1 patients) and for at least 7 months (Arm 2 patients) after the last dose
             of study therapy (chemotherapy or trastuzumab)

          -  Submission of tumor samples from the breast surgery is required for all patients;
             therefore, 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-47 trial

          -  The patient must have signed and dated an Institutional Review Board (IRB)-approved
             consent form that conforms to federal and institutional guidelines

          -  Eastern Cooperation 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, one of the following criteria must be met:

                         -  pT2 and estrogen receptor (ER) negative and progesterone receptor (PgR)
                            negative; or

                         -  pT2 and ER positive (PgR status may be positive or negative) and either
                            grade 3 histology or Oncotype DX Recurrence Score of >= 25; or

                         -  pT3 regardless of hormone receptor status, histologic grade, and
                            Oncotype DX Recurrence Score

          -  HER2 status of the primary tumor must be evaluated prior to randomization; all testing
             performed must indicate that the tumor is HER2-low as defined below

               -  IHC must be performed and the IHC staining results must indicate a score of 1+
                  (in situ hybridization [ISH] testing is not required) or 2+ (ISH must also be
                  performed and must indicate that the tumor is HER2-low as described below)

               -  If ISH testing is performed, test results must be as follows and IHC must be 1+
                  or 2+: the ratio of HER2 to chromosome enumeration probe 17 (CEP17) must be < 2.0
                  or, if a ratio was not performed, the HER2 gene copy number must be < 4 per
                  nucleus

               -  Note: If the IHC staining intensity is reported as a range, e.g., 0 to 1+ or 1+
                  to 2+, the higher intensity score in the range should be used to determine
                  eligibility

          -  The patient must have undergone either a total mastectomy or breast-conserving surgery
             (lumpectomy); (patients who have had a nipple-sparing mastectomy are eligible)

          -  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 may 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 free of gross residual 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, 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 procedures

          -  The interval between the last surgery for breast cancer (treatment or staging) and
             randomization must be no more than 84 days

          -  The patient must have ER analysis performed on the primary tumor prior to
             randomization; if ER analysis is negative, then PgR analysis must also be performed
             (either the core biopsy or surgical resection specimen can be used for ER/PgR
             testing); patients with a primary tumor that is hormone receptor-positive or
             receptor-negative are eligible

          -  Absolute neutrophil count (ANC) must be >= 1,200/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 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 (if alanine
             aminotransferase [ALT] is performed instead of AST [per institution's standard
             practice], the alanine aminotransferase [ALT] value must be =< 1.5 x ULN; if both were
             performed, the AST must be =< 1.5 x ULN)

          -  Alkaline phosphatase and AST may not both be > the 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 above 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 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

          -  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 maybe substituted based on
             institutional preferences

               -  For patients who will receive the TC chemotherapy regimen, the LVEF must be >=
                  50% regardless of the cardiac imaging facility's lower limit of normal

               -  For patients who will receive the AC-->WP chemotherapy regimen, the LVEF must be
                  >= 55% 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 > 70%, 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:

          -  Primary tumor with any of the following HER2 testing results:

               -  IHC staining intensity:

                    -  0 on all evaluations of specimens

                    -  3+ on evaluation of any specimen

               -  ISH with a ratio of HER2 to CEP17 >= 2.0 on evaluation of any specimen

               -  ISH result indicating HER2 gene copy number >= 4 per nucleus on evaluation of any
                  specimen

          -  T4 tumors including inflammatory breast cancer

          -  Definitive clinical or radiologic evidence of metastatic disease

               -  NOTE: 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 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, taxanes, or trastuzumab for any malignancy

          -  Chemotherapy or HER2-targeted therapy administered for the currently diagnosed breast
             cancer prior to randomization

          -  Whole-breast RT prior to randomization or partial-breast RT that cannot be completed
             on or before the date of randomization

          -  Continued endocrine therapy such as raloxifene or tamoxifen (or other selective
             estrogen receptor modulator [SERM]) or an aromatase inhibitor; patients are eligible
             if these medications are discontinued 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

                    -  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)

                    -  Documented cardiomyopathy

          -  Hypertension defined according to the following ineligibility criteria:

               -  For patients who will receive TC (regardless of the patient's age): uncontrolled
                  hypertension defined as sustained systolic blood pressure (BP) > 150 mm Hg or
                  diastolic BP > 90 mm Hg; (patients with initial BP elevations are eligible if
                  initiation or adjustment of BP medication lowers pressure to meet entry criteria)

               -  For patients < 50 years old who will receive AC-->WP: uncontrolled hypertension
                  defined as sustained systolic BP > 150 mm Hg or diastolic BP > 90 mm Hg; patients
                  with initial BP elevations are eligible if initiation or adjustment of BP
                  medication lowers pressure to meet entry criteria

               -  For patients >= 50 years old who will receive AC-->WP:

                    -  Uncontrolled hypertension defined as sustained systolic BP > 150 mm Hg or
                       diastolic BP > 90 mm Hg

                    -  Controlled hypertension (systolic BP =< 150 mm Hg and diastolic BP =< 90
                       mmHg), if anti-hypertensive medication(s) are needed

               -  NOTE: Patients who are not eligible based on the AC-WP regimen BP criteria but
                  who meet the TC regimen BP criteria are eligible for B-47, if the intended
                  chemotherapy regimen is changed to TC

          -  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

          -  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
             methylprednisol one equivalent (excluding inhaled steroids)

          -  Known hypersensitivity to any of the study drugs or excipients, e.g., polysorbate 80
             and Cremophor EL

          -  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