Dasatinib In Combination With Trastuzumab And Paclitaxel In First Line Treatment Of Her2-Positive MBC Patients

This is a single-arm, open-label, phase I/II study. In the phase I, patients with Human Epidermal Growth Factor Receptor 2 (HER2) positive MBC will be treated with paclitaxel, trastuzumab and increasing doses of dasatinib to determine the Maximum Tolerated Dose (MTD), Dose Limiting Toxicity (DLT) and Recommended Phase II Dose (RPD) of the combination. Once the RPD has been identified, 48 patients will be treated at that dose to evaluate the efficacy and safety of the combination in the phase II.

Eligible patients will be enrolled and treated with 4-week cycles of trastuzumab 2 mg/kg IV weekly (following a loading dose of 4 mg/kg in cycle 1) and paclitaxel 80 mg/m2 weekly x 3 weeks followed by a rest period of 7 days. Dasatinib will be administered orally in two dose levels 100 and 140 mg once daily (a -1 dose level is included just in case dose de-escalation is needed). Treatment will be repeated on Day 1 of a 28-day cycle in all patients (both in the phase I as in the phase II) until radiographic or symptomatic progression or unacceptable toxicity occurs. Only in the phase I and in all patients included in every different dose level, the first cycle will last 38 days.

Primary Objective:

* To determine the maximum tolerated dose (MTD) and recommended phase II dose (RPD) of dasatinib in combination with fixed doses of trastuzumab and paclitaxel in HER2-positive MBC patients (Phase I).
* To determine the efficacy, measured by objective response rate (ORR) in HER2-positive MBC patients with measurable disease (Phase II).

Secondary Objective(s):

* To characterize the safety of the combination (in both phase I and phase II).
* To evaluate the Clinical Benefit Rate (CBR), Time to Progression (TTP), Progression Free Survival (PFS) and Response Duration (RD) (in the phase II).
* To evaluate the pharmacokinetics (PK) of the combination (in the phase I and selected patients in the phase II if necessary).
* To evaluate molecular characteristics that may be predictive of the activity (or lack of) and any correlation between the biological activity of the study treatment and the disease outcome.

Exploratory objective:

• To explore the correlation between the lymphocytosis and efficacy.

Sample Size:

Phase I: following the 3+3 rule, a minimum of 6 and a maximum of 12 patients will be recruited.

Phase II:Assuming 10% drop-out rate, 48 patients are required to enter the study.

The duration of the study, from first patient visit to last patient visit will be approximately 42 months.

Eligibility Criteria:
Inclusion Criteria:

1. Female with histologically confirmed breast cancer with documented metastasis.
2. Patients must have Human Epidermal Growth Factor Receptor 2 (HER2) 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.
3. 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.
4. Signed Written Informed Consent.
5. Target Population:

   1. Patients with Performance Status (ECOG) of 0 or 1.
   2. Number of previous therapies allowed or previous therapies may have included:

      * 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.
      * Hormonal Therapy: patients may have had prior hormonal therapy. All hormonal agents must be discontinued at least 3 weeks prior to study entry.
      * 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.
      * Previous Surgery: previous surgery is permitted provided that wound healing has occurred.
      * 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.
   3. Adequate Organ Function (...).
   4. Ability to take oral medication (dasatinib must be swallowed whole).
   5. Concomitant Medications

   i) Patient agrees to discontinue St. Johns Wort while receiving dasatinib therapy (discontinue St. Johns Wort at least 5 days before starting dasatinib) ii) Biphosphonates must not be initiated within 28 days prior to study therapy
6. Age and sex:

   f) Patient, age 18 years old. g) Women of childbearing potential (WOCBP) must be using an adequate method of contraception to avoid pregnancy throughout the study and for at least 4 weeks after the last dose of study drug to minimize the risk of pregnancy. (...)

Exclusion Criteria:

1. Sex and reproductive status:

   1. WOCBP who are unwilling or unable to use an acceptable method to avoid pregnancy for the entire study period and for at least 4 weeks after the last dose of study drug
   2. Women who are pregnant or breastfeeding.
   3. Women with a positive pregnancy test
2. Target Disease Exceptions:

   a) Central nervous system (CNS) metastases which are not well controlled. Eligible patients must be asymptomatic, cannot be receiving steroids or anticancer treatment, and must be enrolled at least 1 month after the end of the radiotherapy treatment
3. Medical History and Concurrent Diseases

   1. No malignancy \[other than the one treated in this study\] which required radiotherapy or systemic treatment within the past 5 years.
   2. Concurrent medical condition which may increase the risk of toxicity, including: Pleural or pericardial effusion of any grade.
   3. Cardiac Symptoms; any of the following should be considered for exclusion:

   i) Uncontrolled angina, congestive heart failure or myocardial infarction (MI) within (6 months) ii). Patients with intercurrent cardiac dysfunction or left ventricular ejection fraction (LVEF) \< 50%.

   iii) Diagnosed congenital long QT syndrome. iv) Any history of clinically significant ventricular arrhythmias (such as ventricular tachycardia, ventricular fibrillation, or Torsades de pointes).

   v) Prolonged corrected QT (QTc) interval on pre-entry electrocardiogram (450 msec).

   vi) Patients with hypokalemia or hypomagnesemia if it cannot be corrected prior to dasatinib administration.

   d) History of significant bleeding disorder unrelated to cancer, including: i) Diagnosed congenital bleeding disorders (e.g., von Willebrand's disease). ii) Diagnosed acquired bleeding disorder within one year (e.g., acquired anti-factor VIII antibodies).

   iii) Ongoing or recent (≤ 3 months) significant gastrointestinal bleeding.
4. Allergies and Adverse Drug Reactions

   a) Patients with known allergy to any of the study drugs or their components.
5. Prohibited Treatments and/or Therapies

   a) Category I drugs that are generally accepted to have a risk of causing Torsades de Pointes including: (Patients must discontinue drug 7 days prior to starting dasatinib) i) quinidine, procainamide, disopyramide ii) amiodarone, sotalol, ibutilide, dofetilide iii) erythromycin, clarithromycin iv) chlorpromazine, haloperidol, mesoridazine, thioridazine, pimozide v) cisapride, bepridil, droperidol, methadone, arsenic, chloroquine, domperidone, halofantrine, levomethadyl, pentamidine, sparfloxacin, lidoflazine.

   b) Concurrent anti-cancer therapy c) Potent CYP3A4 inhibitors
6. Other exclusion criteria:

   1. Patients who are compulsorily detained for treatment of either a psychiatric or physical (eg, infectious disease) illness.
   2. Patients with active or uncontrolled infections or with serious illnesses or medical conditions that would not permit the patient to be managed according to the protocol.
   3. Patients unable or unwilling to give written informed consent prior to study participation.
   4. Pre-existent motor or sensory neurotoxicity of severity ≥ grade 2 according to NCI common toxicity criteria (version 4.03).