Lapatinib +/- Trastuzumab In Addition To Standard Neoadjuvant Breast Cancer Therapy.
Condition: Neoplasms, Breast
MeSH terms: Breast Neoplasms
Intervention: Trastuzumab; Paclitaxel; FEC75; Lapatinib
Intervention description: 4mg/kg IV loading dose followed by 2mg/kg IV weekly; 80mg/m2 IV weekly for 4 (21 day) cycles; 5FU 500mg/m2 + Epirubicin 75 mg/m2 + cyclophosphamide 500 mg/m2 IV on day 1 of 4 (21 day) cycles; 1250 mg oral daily dose in arm 2, 750 mg oral daily dose for FEC cycles and then 1000 mg oral daily dose during the Paclitaxel cycles in arm 3
Intervention MeSH terms: Paclitaxel; Trastuzumab; Lapatinib
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 100.0
Sex: Female
Minimum age: 18 Years
Healthy volunteers: No
Keywords: ErbB2 Overexpressing; ErbB2 Positive; Lapatinib; Invasive Breast Cancer

Summary:

      This study will examine safety and efficacy of Lapatinib in combination with a standard
      neoadjuvant chemotherapy including 5FU, Epirubicin, Cyclophosphamide and Paclitaxel. Tumor
      tissue will be obtained at 3 timepoints (optional 4th) to evaluate tumor response to
      treatment.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Have signed an informed consent form (ICF) and a Patient Authorization Form (HIPAA).

          -  Have histologically or cytologically confirmed ErbB2- (HER2/neu-) overexpressing
             invasive breast cancer (T2-4, N0-2).

          -  ErbB2 overexpressing breast cancer, defined as one of the following definitions:

          -  3+ staining by immunohistochemistry (IHC),

          -  a fluorescent in situ hybridization (FISH) result of more than six HER2 gene copies
             per nucleus

          -  a FISH ratio of more than 2.2.

          -  Have either measurable or evaluable disease.

          -  Have an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-1
             (Refer to Section 11.4).

          -  Have LVEF within the institutional range of normal as measured by either
             echocardiogram (ECHO) or MUGA scans. The same modality must be used consistently
             throughout the study.

          -  Be deemed able to tolerate 8 cycles of preoperative chemotherapy, including 4 cycles
             with an anthracycline (epirubicin).

          -  Must be willing to undergo 2 mandatory core biopsies (4 passes each) after diagnosis
             to obtain tissue for biologic expression profiling. Any subject with clinically
             palpable residual disease may undergo an optional third biopsy to allow identification
             of presumed pathways of resistance to therapy. This information might be useful in
             providing the subject with options for other targeted therapies if definitive surgery
             confirms residual disease. Definitive local therapy with surgery and radiation therapy
             as indicated will be performed after completion of 12 weeks of paclitaxel-based
             chemotherapy.

          -  Are able to swallow and retain oral medication (intact pill).

          -  Are able to complete all screening assessments as outlined in the protocol.

          -  Have adequate organ function as defined in Table 4:

        Table 1 Baseline Laboratory Values

        Hematologic:

        ANC (absolute neutrophil count) >1.5 x 109/L hemoglobin >9 g/dL platelets >75 x 109/L

        Hepatic:

        albumin >2.5 g/dL serum bilirubin <1.25 x ULN AST / ALT <3 x ULN if no documented liver
        metastases AST / ALT <3 x ULN with documented liver metastases

        Renal:

        serum creatinine <2.0 mg/dL

          -  OR - calculated creatinine clearance >40 mL/min

          -  Are subjects aged >18 years with any menopausal status:

        Non-child-bearing potential (i.e., women with functioning ovaries who have a current
        documented tubal ligation or hysterectomy, or women who are postmenopausal)

        Child-bearing potential (i.e., women with functioning ovaries and no documented impairment
        of oviductal or uterine function that would cause sterility.) This category includes women
        with oligomenorrhea (severe), women who are perimenopausal, and young women who have begun
        to menstruate. These subjects must have a negative serum pregnancy test at screening and
        agree to one of the following:

        Complete abstinence from intercourse from 2 weeks prior to administration of the first dose
        of study medication until 28 days after the final dose of study medication; or Consistent
        and correct use of one of the following acceptable methods of birth control: male partner
        who is sterile prior to the female subject's entry into the study and is the sole sexual
        partner for that female subject; any intrauterine device (IUD) with a documented failure
        rate of less than 1% per year; oral contraceptives (either combined or progestogen only)
        where not contraindicated for this subject population or per local practice.; or barrier
        methods, including diaphragm or condom with a spermicide.

        Please note that breast cancer subjects on this trial cannot receive injectable
        levonorgestrel or injectable progestogen due to the potential for an adverse effect of
        anti-hormonal therapies on chemotherapy administered for breast cancer [Albain, 2002].
        Progestogen may also affect the proliferative rate of endocrine-responsive tumors.

        Exclusion Criteria:

          -  Have received any prior chemotherapy.

          -  Had prior therapy with an ErbB1 and/or ErbB2 inhibitor.

          -  Are receiving concurrent anti-cancer therapy (chemotherapy, immunotherapy, and
             biologic therapy) while taking study medication.

          -  Have malabsorption syndrome, disease significantly affecting gastrointestinal
             function, or resection of the stomach or small bowel. Women with ulcerative colitis
             are also excluded.

          -  Have a concurrent disease or condition that would make the woman inappropriate for
             study participation, or any serious medical disorder that would interfere with the
             woman's safety.

          -  Have an active or uncontrolled infection.

          -  Have dementia, altered mental status, or any psychiatric condition that would prohibit
             the understanding or rendering of informed consent.

          -  Have active cardiac disease, defined as one or more of the following:

        History of uncontrolled or symptomatic angina History of arrhythmias requiring medications,
        or clinically significant Myocardial infarction <6 months from study entry Uncontrolled or
        symptomatic congestive heart failure Ejection fraction below the institutional normal limit
        Any other cardiac condition, which in the opinion of the treating physician, would make
        this protocol unreasonably hazardous for the patient

          -  Are pregnant or breastfeeding.

          -  Have received concurrent treatment with an investigational agent or participate in
             another clinical trial.

          -  Have received concurrent treatment with prohibited medications (refer to Section 5.8.2
             for details on prohibited medications).

          -  Have used an investigational drug within 30 days or 5 half-lives, whichever is longer,
             preceding the first dose of study medication.

          -  Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs
             chemically related to any of the agents used in this study or their excipients.

          -  Are receiving therapeutic anti-coagulation therapy (i.e. warfarin, heparin).