Trastuzumab Versus Lapatinib as Neoadjuvant Treatment for Her2+ Patients
Condition: Breast Cancer
MeSH terms: Breast Neoplasms
Intervention: Epirubicin; Cyclophosphamide; Docetaxel; Lapatinib; Trastuzumab
Intervention MeSH terms: Cyclophosphamide; Docetaxel; Trastuzumab; Epirubicin; Lapatinib
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 102.0
Sex: Female
Minimum age: 18 Years
Healthy volunteers: No
Keywords: HER2-positive breast cancer; Lapatinib; Neoadjuvant; Trastuzumab; Biomarkers

Summary:

      Phase II randomized multicenter trial to compare Epirubicin and Cyclophosphamide plus
      Docetaxel and Trastuzumab with Epirubicin and Cyclophosphamide plus Docetaxel and Lapatinib
      for patients with positive HER2 and resectable or locally advanced breast cancer.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Signature of the written informed consent.

          2. Histological documentation of breast cancer.

          3. Stage I (T1, N0M0), IIA (T2N0M0); IIB (T2N1M0, T3N0M0), IIIA (TXN2M0) and IIIB
             (T3N1M0, T4NXM0) primary resectable breast cancer or locally advanced breast cancer.

          4. HER2-positive breast cancer, defined as immunohistochemistry (IHQ) 3+ or positive
             FISH. When IHQ 2+ HER2 status must be assessed by FISH.

          5. The patient granted her consent for taking a biopsy before treatment

          6. The patient granted her consent for sending two tumor samples to central laboratory
             for molecular sub study.

          7. Two weeks prior randomization pregnancy test negative for women of childbearing
             potential.

          8. Women of childbearing potential must use adequate contraceptive measures during
             participation into study. Oral, injectable or implant hormonal contraceptives measure
             are not permitted.

          9. A World Health Organization (WHO) performance status of 0 or 1 (Karnofsky ≥ 80)

         10. Age > 18 years.

         11. Absence of metastases disease

         12. Baseline Electrocardiography (EKG) 12 weeks prior to randomization. Baseline left
             ventricular ejection fraction (LVEF) value within limit of normal value for the
             institution or > 50% of basal value

         13. Normal laboratory test 2 weeks prior to randomization:

             Haematology values: Neutrophil count ≥ 1,5 x109/l; Platelets ≥ 100 x 109/l;
             Haemoglobin ≥ 10mg/dl Biochemistry values: serum total bilirubin ≤ 1 x Upper Limit of
             Normal (ULN); Aspartate aminotransferase (AST) (SGOT) and Alanine aminotransferase
             (ALT) (SGPT) ≤ 2,5 x ULN; alkaline phosphatase ≤ 5 x ULN. Patients which AST and/or
             ALT value are > 1,5 x ULN along with alkaline phosphatase value > 2,5 x ULN will be
             not included into the study.

             Renal function: serum creatinine ≤ 175 µmol/l (2 mg/dl). If the value is borderline,
             clearance creatinine must be ≥ 60 ml/min

         14. 12 weeks prior to randomization the following assessments and procedures must be
             fulfilled: Bilateral mammography; Magnetic resonance imaging (MRI) Breast and
             axillary; Chest X-Ray (posterioanterior and lateral); Abdominal ultrasound; Chest
             CT-Scan; Abdominal CT-Scan. Bone Scan (if applicable)

         15. Patients must be accessible for treatment and follow up

        Exclusion Criteria:

          1. Patients with lumpectomy, partial mastectomy, modified radical mastectomy are not
             allowed to include into study.

          2. Prior Immunotherapy, hormonal therapy and chemotherapy for breast cancer is not
             allowed.

          3. Prior therapy with anthracycline and taxanes (paclitaxel and docetaxel) is not
             permitted for any neoplasia.

          4. Prior radiotherapy for breast cancer.

          5. Bilateral invasive breast carcinoma

          6. Pregnant or nursing patients. Negative pregnant test (serum or urine) 14 days prior to
             randomization.

          7. HER 2 negative breast cancer

          8. Patients of childbearing potential must be use adequate contraceptive measures during
             study treatment. No hormonal contraceptive measure is permitted.

          9. Any M1 breast cancer

         10. Any motor or sensorial neurotoxicity grade ≥ 2 according to National Cancer Institute
             Common Terminology Criteria for Adverse Events (NCI CTCAE) version 3.

         11. Serious cardiac illness or medical conditions: Congestive heart failure, angina
             pectoris requiring specific treatment, myocardial infarction 1 year prior to enroll in
             the study; poorly controlled hypertension or high-risk uncontrolled arrhythmias.

             History of significative neurological or psychiatric disease (psychotic, dementia or
             attack) what is unable to patient to grant her informed consent.

             Uncontrolled severe Infection Uncontrolled diabetes mellitus, active peptic ulcer

         12. Current malignancy or previous malignancy other that breast cancer. Exception cell
             carcinoma of the skin no melanoma, carcinoma in situ of the cervix or any other cancer
             in the past 10 years.

         13. Long term treatment with corticoids except 6 months prior to inclusion in the study
             and low doses (≤ 20 mg methylprednisolone or equivalent)

         14. Corticoid use contraindication

         15. Concomitant hormonal replacement therapy. Previous treatment should be interrupted
             before inclusion into study.

         16. Cardiopathy what stops patient taking Docetaxel and Trastuzumab: myocardial infarction
             recorded; angina pectoris requiring specific treatment; any congestive heart failure
             recorded; arrhythmia grade 3 or 4 according to NCI CTCAE version 3; any relevant
             valvular disease; chest X ray which shows cardiomegaly or EKG which shows ventricular
             hypertrophy unless LVEF value has been ≥ lower normal limit in the last 3 months.

         17. Poorly controlled hypertension (systolic > 180 mm Hg or diastolic > 100 mm Hg). The
             patients with controlled hypertension under treatment can be included into study

         18. Patients under treatment of arrhythmia, angina or congestive heart failure with drug
             which modifies cardiac conduction (after digital, beta blocker or inhibitors calcium
             channel) are excluded. However if these drugs are took for arterial tension the
             patient can be included into study.

         19. The patient must interrupt concomitant treatment with hormonal therapy ej. raloxifene,
             tamoxifen and selective estrogen receptor modulators (SERM) prior to randomization.

         20. Concomitant use of inhibitors and inductors of enzyme CYP3A4 complex (ketoconazole,
             itraconazole or grape juice; rifampicin, carbamazepin or fenitoin) are not permitted.
             Also, drug are substrate of enzyme CYP2C8 complex is not permitted along with
             lapatinib treatment.

         21. Concurrent treatment with an investigational agent or participation in another
             therapeutic clinical trial within 30 days prior to randomization into study.

         22. Concomitant treatment with other anticancer therapy

         23. Hypersensitivity reaction to drugs trastuzumab, lapatinib or their excipients.

         24. Male