Comparison of Neoadjuvant Chemotherapy With Weekly Paclitaxel or Eribulin Followed by A/C in Women With Locally Advanced HER2-Negative Breast Cancer
Condition: Breast Cancer; HER2-negative Breast Cancer
MeSH terms: Breast Neoplasms
Intervention: Paclitaxel; Eribulin; Doxorubicin; Cyclophosphamide
Intervention description: 80 mg/m2 IV over 60 minutes weekly for 12 weeks; 1.4 mg/m2 IV over 2 to 5 minutes on Days 1 and 8 every 21 days for 4 cycles; 60 mg/m2 IV over 15 minutes on day 1 every 21 days for 4 cycles; 600 mg/m2 IV over 30 minutes on day 1 every 21 days for 4 cycles
Intervention MeSH terms: Paclitaxel; Cyclophosphamide; Doxorubicin
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 50.0
Sex: Female
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      NSABP FB-9 is a Phase II, multi-center, randomized study of eribulin or weekly paclitaxel
      followed by doxorubicin and cyclophosphamide (AC) as neoadjuvant therapy for women with
      HER2-negative, operable and locally advanced breast cancer (stage IIb and III). Patients in
      the control arm will receive neoadjuvant weekly paclitaxel (WP) followed by AC. The primary
      aim of the study is to determine the pathologic complete response (ypCR) in breast and
      axillary lymph nodes following completion of neoadjuvant therapy. The secondary aims include
      determination of the ypCR in axillary nodes, clinical complete response (ycCR) rate after
      eribulin or paclitaxel and after completion of neoadjuvant chemotherapy, two-year
      recurrence-free interval, two-year overall survival, and toxicity of the neoadjuvant
      regimens.
    

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.)

          -  Patients of reproductive potential must agree to use an effective non-hormonal method
             of contraception during therapy and for at least 6 months after the last dose of study
             therapy.

          -  The patient must have consented to participate and must have signed and dated an
             appropriate Institutional Review Board (IRB)-approved consent form that conforms to
             federal and institutional guidelines.

          -  Patients must be female.

          -  Patients must be > 18 years old.

          -  The Eastern Cooperative Oncology Group (ECOG) performance status must be 0 or 1.

          -  The diagnosis of invasive adenocarcinoma of the breast must have been made by core
             needle biopsy or by limited incisional biopsy.

          -  Patients must have ER analysis performed on the primary tumor prior to randomization.
             If ER analysis is negative, then Progesterone Receptor (PgR) analysis must also be
             performed. (Patients are eligible with either hormone receptor-positive or hormone
             receptor-negative tumors.)

          -  Clinical staging, based on the assessment by physical exam, must be American Joint
             Committee on Cancer (AJCC) stage IIB, IIIA, IIIB, or IIIC: cT2 and cN1, cT3 and cN0 or
             cN1, Any cT and cN2 or cN3, cT4

          -  The patient must have a mass in the breast or axilla measuring greater than or equal
             to 2.0 cm by physical exam, unless the patient has inflammatory breast cancer, in
             which case measurable disease by physical exam is not required.

          -  At the time of randomization, blood counts performed within 4 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; Hemoglobin must be greater than or equal to 10 g/dL.

          -  The following criteria for evidence of adequate hepatic function performed within 4
             weeks prior to randomization must be met: total bilirubin must be less than or equal
             to 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; and alkaline phosphatase must be less than or equal to
             1.5 x ULN for the lab; and Aspartate aminotransferase (AST) and Alanine
             aminotransferase (ALT) must be less than or equal to 1.5 x ULN for the lab.

          -  Patients with alkaline phosphatase > ULN but less than or equal to 1.5 x ULN are
             eligible for inclusion in the study if liver imaging (CT, MRI, PET, or PET-CT scan)
             performed within 4 weeks prior to randomization does not demonstrate metastatic
             disease and the requirements in the criteria below for unexplained skeletal pain are
             met.

          -  Patients with either unexplained skeletal pain or alkaline phosphatase that is > ULN
             but less than or equal to 1.5 x ULN are eligible for inclusion in the study if a bone
             scan, PET-CT scan, or PET scan performed within 4 weeks prior to randomization does
             not demonstrate metastatic disease. Patients with suspicious findings on bone scan or
             PET scan are eligible if suspicious findings are determined to be benign by x-ray,
             MRI, or biopsy.

          -  Serum creatinine performed within 4 weeks prior to randomization must be less than or
             equal to 1.5 x ULN for the lab.

          -  Serum potassium and serum magnesium performed within 4 weeks prior to randomization
             must be Within Normal Limits (WNL).

          -  The Left Ventricular Ejection Fraction (LVEF) assessment by 2-D echocardiogram or
             Multigated acquisition (MUGA) scan performed within 90 days prior to randomization
             must be greater than or equal to 50% regardless of the facility's Lower Limit of
             Normal (LLN).

          -  ECG performed within 4 weeks before study entry must demonstrate a QTc interval that
             is less than or equal to 0.47 seconds.

        Exclusion Criteria:

          -  Tumor that has been determined to be HER2-positive by immunohistochemistry (3+) or by
             in situ hybridization (positive for gene amplification), or has been determined to be
             HER2-equivocal and the investigator plans to administer trastuzumab or other targeted
             therapy.

          -  Fine Needle Aspiration (FNA) alone to diagnose the primary breast cancer.

          -  Excisional biopsy or lumpectomy performed prior to randomization.

          -  Surgical axillary staging procedure prior to randomization. (Procedures that are
             permitted prior to study entry include: 1) FNA or core biopsy of an axillary node for
             any patient, and 2) although not recommended, a pre-neoadjuvant therapy Sentinal Node
             (SN) biopsy for patients with clinically negative axillary nodes.)

          -  Definitive clinical or radiologic evidence of metastatic disease. (Note: Chest imaging
             is mandatory for all patients within 90 days prior to randomization. Other imaging [if
             required] must have been performed within 4 weeks prior to randomization.)

          -  History of ipsilateral invasive breast cancer regardless of treatment or ipsilateral
             Ductal Carcinoma in Situ (DCIS) treated with Radiation Therapy (RT). (Patients with a
             history of Lobular Carcinoma in Situ (LCIS), contralateral DCIS [regardless of RT], or
             contralateral invasive breast cancer 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.

          -  Known metastatic disease from any malignancy (solid tumor or hematologic).

          -  Previous therapy with anthracyclines, taxanes, cyclophosphamide, or eribulin for any
             malignancy.

          -  Treatment including RT, chemotherapy, and/or targeted therapy, 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 continued sex hormonal therapy, e.g., birth control pills and ovarian hormone
             replacement therapy. Patients are eligible if these medications are discontinued prior
             to randomization.

          -  Requirement for chronic use of any drugs known to prolong the QT interval, including
             Na+ and K+ channel blockers. (Patients are eligible if these medications and/or
             substances can be discontinued prior to the first dose of eribulin and will not need
             to be resumed until after the last dose of eribulin.)

          -  Active hepatitis B or hepatitis C with abnormal liver function tests.

          -  Intrinsic lung disease resulting in dyspnea.

          -  Active infection; or chronic infection requiring chronic suppressive antibiotics.

          -  Persistent greater than or equal to grade 2 diarrhea regardless of etiology.

          -  Sensory or motor neuropathy greater than or equal to grade 2, as defined by the NCI
             Common Toxicity Criteria for Adverse Effects (CTCAE) v4.0.

          -  Conditions that would prohibit intermittent administration of corticosteroids for
             paclitaxel premedication.

          -  Chronic daily treatment with corticosteroids with a dose of greater than or equal to
             10 mg/day methylprednisolone equivalent (excluding inhaled steroids).

          -  Uncontrolled hypertension defined as a systolic BP > 150 mmHg or diastolic BP > 90
             mmHg, with or without anti-hypertensive medications. (Patients with hypertension that
             is well-controlled on medication are eligible.)

          -  Cardiac disease (history of and/or active disease) that would preclude the use of any
             of the drugs included in the treatment regimen. This includes but is not confined to:
             Active cardiac disease: symptomatic angina pectoris within the past 180 days that
             required the initiation of or increase in anti-anginal medication or other
             intervention; 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) documented
             cardiomyopathy; and congenital long QT syndrome.

          -  Other nonmalignant systemic disease that would preclude the patient from receiving
             study treatment or would prevent required follow-up.

          -  Pregnancy or lactation at the time of randomization.

          -  Any psychiatric or addictive disorder or other condition that, in the opinion of the
             investigator, would preclude her from meeting the study requirements.

          -  Use of any investigation agent within 4 weeks prior to randomization.