Phase II Randomized Trial Evaluating Neoadjuvant Therapy With Neratinib and/or Trastuzumab Followed by Postoperative Trastuzumab in Women With Locally Advanced HER2-positive Breast Cancer
Condition: Breast Cancer
MeSH terms: Breast Neoplasms
Intervention: Paclitaxel; Trastuzumab; Neratinib; Doxorubicin; Cyclophosphamide
Intervention MeSH terms: Paclitaxel; Cyclophosphamide; Doxorubicin; Trastuzumab
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 141.0
Sex: Female
Minimum age: 18 Years
Healthy volunteers: No
Keywords: breast cancer; neoadjuvant; neratinib; paclitaxel; trastuzumab; doxorubicin; cyclophosphamide

Summary:

      FB-7 is a Phase II, multi-center randomized study of neratinib in combination with weekly
      paclitaxel with or without trastuzumab followed by doxorubicin and cyclophosphamide (AC) as
      neoadjuvant therapy for women with HER2-positive locally advanced breast cancer. Patients in
      the control arm will receive neoadjuvant trastuzumab in combination with weekly paclitaxel
      followed by AC. The primary aim of the study is to determine the pathologic complete response
      (pCR) rate in breast and axillary nodes following the neoadjuvant therapy regimens. The
      secondary aims include determination of the pCR rate in breast only, clinical complete
      response (cCR) rate, two-year recurrence-free interval, two-year overall survival, toxicity
      of the neoadjuvant regimens, and exploration of molecular and genetic correlates of response.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Patients should have a life expectancy of at least 10 years, excluding their diagnosis
             of breast cancer.

          -  Submission of a block from the diagnostic biopsy sample and from the surgical sample,
             if gross residual disease greater than or equal to 1.0 cm was removed at the time of
             surgery, is required for all patients

          -  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 Eastern Cooperative Oncology Group (ECOG) performance status must be 0 or 1.

          -  Patients must have the ability to swallow oral medication.

          -  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.)

          -  Breast cancer must be determined to be HER2-positive prior to randomization. Assays
             using FISH or CISH require gene amplification. Assays using IHC require a strongly
             positive (3+) staining score.

          -  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; or 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 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 aminotransferase (AST) and ALT must be
             less than or equal to 1.5 x ULN for the lab.

          -  Patients with alkaline phosphatase greater than ULN but less than or equal to 2.5 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 for adequate hepatic function are met.

          -  Patients with either unexplained skeletal pain or 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 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.

          -  The left ventricular ejection fraction (LVEF) assessment by 2-D echocardiogram or
             multiple gated acquisition(MUGA) scan performed within 90 days prior to randomization
             must be greater than or equal to 50% regardless of the facility's LLN.

        Exclusion Criteria:

          -  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 SN biopsy for
             patients with clinically negative axillary nodes.)

          -  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.)

          -  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 LCIS are eligible.)

          -  Contralateral invasive breast cancer at any time. (Patients with contralateral DCIS or
             lobular carcinoma in situ (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.

          -  Known metastatic disease from any malignancy (solid tumor or hematologic).

          -  Previous therapy with anthracyclines, taxanes, cyclophosphamide, trastuzumab, or
             neratinib 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.

          -  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.

          -  Malabsorption syndrome, ulcerative colitis, inflammatory bowel disease, resection of
             the stomach or small bowel, or other disease or condition significantly affecting
             gastrointestinal function.

          -  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) v3.0.

          -  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 greater than 150 mmHg or diastolic
             BP greater than 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 LV function;
             history of documented congestive heart failure (CHF); and documented cardiomyopathy.

          -  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.

          -  The investigator should assess the patient to determine if she has 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 investigational agent within 4 weeks prior to randomization.