Dasatinib In Combination With Trastuzumab And Paclitaxel In The First Line Treatment Of Her2-Positive Metastatic Breast Cancer (MBC) Patients

Inclusion Criteria:

• Female with histologically confirmed breast cancer with documented metastasis.

  • Patients must have HER-2 overexpression by immunohistochemistry (3+, Herceptest; DAKO) or a positive fluorescence in situ hybridization for HER2 amplification evaluated by central laboratory. It is recommended that a formalin-fixed paraffin embedded (FFPE) tumor tissue block from the metastatic site (or the primary tumor, if metastatic site not available) required for HER2 testing are provided.
  • Patients can have measurable or non measurable disease for the Phase I part. For the Phase II only patients with measurable disease defined per RECIST 1.1 will be included.
  • Signed Written Informed Consent.
  • Patients with Performance Status (ECOG) of 0 or 1.

  • Number of previous therapies allowed or previous therapies may have included:

    1. Chemotherapy: no prior chemotherapy for MBC is permitted. Patients treated with adjuvant chemotherapy regimens based on taxanes are allowed to be included if they are fully recovered of any taxane associated toxicity and a minimum of 12 months have elapsed from the end of this therapy.
    2. Hormonal Therapy: patients may have had prior hormonal therapy. All hormonal agents must be discontinued at least 3 weeks prior to study entry.
    3. Radiation Therapy: patients may have had prior radiation therapy that has not exceeded 25% of the bone marrow reserve. A minimum of 21 days must have elapsed between the last dose of radiation and registration into the study. Patients must have recovered from any acute toxic effects from radiation prior to registration. Lesions that have been irradiated cannot be included as sites of measurable disease for the phase II unless clear tumor progression, according to RECIST criteria, has been documented in these lesions since the end of radiation therapy.
    4. Previous Surgery: previous surgery is permitted provided that wound healing has occurred.
    5. Anti-HER2 Therapies: no prior anti-HER2 therapy for MBC is permitted. Patients treated with adjuvant anti-HER2 therapies (including but not limited to trastuzumab and lapatinib) are allowed to be included if a minimum of 12 months have elapsed from the end of this therapy.
  • Adequate Organ Function.
  • Ability to take oral medication (dasatinib must be swallowed whole).
  • Patient, age 18 years old.
  • Women of childbearing potential (WOCBP) must be using an adequate method of contraception to avoid pregnancy.

Exclusion Criteria:

• Women who are pregnant or breastfeeding.
• Patients with known brain metastases.
• No malignancy [other than the one treated in this study] which required radiotherapy or systemic treatment within the past 5 years.
• Concurrent medical condition which may increase the risk of toxicity, including: Pleural or pericardial effusion of any grade.

• Cardiac Symptoms; any of the following should be considered for exclusion:

  1. Uncontrolled angina, congestive heart failure or MI within (6 months)
  2. Patients with intercurrent cardiac dysfunction or LVEF < 50%.
  3. Diagnosed congenital long QT syndrome.
  4. Any history of clinically significant ventricular arrhythmias (such as ventricular tachycardia, ventricular fibrillation, or Torsades de pointes).
  5. Prolonged QTc interval on pre-entry electrocardiogram (450 msec).
  6. Patients with hypokalemia or hypomagnesemia if it cannot be corrected prior to dasatinib administration.

• History of significant bleeding disorder unrelated to cancer, including:

  1. Diagnosed congenital bleeding disorders (e.g., von Willebrand's disease).
  2. Diagnosed acquired bleeding disorder within one year (e.g., acquired anti-factor VIII antibodies).
  3. Ongoing or recent (3 months) significant gastrointestinal bleeding.
• Patients with known allergy to any of the study drugs or their components.
• Pre-existent toxicities of severity grade 2 due to previous anti-cancer treatments.