Neoadjuvant Dose-Dense For Early Her2Neu Positive Breast Cancer
Condition: Locally Advanced Breast Cancer
MeSH terms: Breast Neoplasms
Intervention: Docetaxel; Carboplatin; Trastuzumab; Pertuzumab; Pegfilgrastim; Trastuzumab; Paclitaxel; Doxorubicin; Cyclophosphamide; Paclitaxel
Intervention description: Docetaxel 75mg/m2 IV, day 1; Carboplatin AUC 6 IV, day 1; Trastuzumab 8mg/kg IV initial dose, followed by 6mg/kg IV , day 1; Pertuzumab 840 mg IV initial dose followed by 420 mg IV, day 1; Pegfilgrastim 6mg SC, day 2 Cycled as per arm; Trastuzumab 6mg/kg every 21 days to complete 1 year; Titrate the infusion rate on the initial Paclitaxel dose (40 ml/hr x 5 min, then 80 ml/hr x 5 min, then 120 ml/hr x 10 min, then 200 ml/hr). Subsequent Paclitaxel doses are given over 1 hour.; Doxorubicin 60 mg/m2 IV day 1; Cyclophosphamide 600 mg/m2 IV day 1; 80 mg/m2 IV x 1 hour infusion on days 1, 8, and 15
Intervention MeSH terms: Paclitaxel; Docetaxel; Albumin-Bound Paclitaxel; Cyclophosphamide; Carboplatin; Doxorubicin; Trastuzumab; Pertuzumab
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 7.0
Sex: Female
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Neoadjuvant chemotherapy; locally advanced breast cancer; Her2neu

Summary:

      Primary Objective:

      • Determination of pathologic complete response (pCR) rates

      Secondary Objective:

        -  Determination of cardiac toxicity as measured by: composite of LVEF, longitudinal strain
           and troponin.

        -  Breast conservation rates

        -  Overall survival

      Study Design

        -  Approximately 34-74 patients with Her2 positive, Stage II-regional IV breast cancer will
           be enrolled.

        -  Patients will be stratified by ER/PR status.

        -  They will be randomized to ddACTHP vs TCHP.

             -  Initially, 17 patients will be randomly assigned to each treatment arm.

             -  If 3 or fewer patients have a pCR, then that arm will be terminated and no further
                patients will be entered on that treatment arm.

             -  If 4 or more patients obtain a pCR, 20 additional patients (total of 37 patients)
                will be randomized to that treatment arm.

             -  If 11 or more patients out of 37 have a pCR, the treatment will be of interest for
                further study.
    

Eligibility criteria:

        Inclusion Criteria:

        The patient must have signed and dated an IRB-approved consent form that conforms to
        federal and institutional guidelines.

          -  Female

          -  18 years or older

          -  ECOG performance status of 0 or 1

          -  Eligible tumors must meet one of the following criteria:

               -  Operable (T1c, T2-3, N0-1, M0)

               -  Locally advanced (T2-3, N2-3, M0 or T4a-c, any N, M0)

               -  Inflammatory breast cancer (T4d, any N, M0)

          -  Staging evaluation:

               -  History and physical exam, cbc, chemistry profile

               -  CT Chest/Abdomen/Pelvis and a bone scan or PET/CT as needed

          -  Diagnosis of invasive adenocarcinoma made by core needle biopsy

          -  Breast cancer determined to be:

          -  Confirmed HER2-positive : (ASCO CAP guidelines, 10/7/2013)

               -  IHC 3+ based on circumferential membrane staining that is complete, intense

               -  ISH positive based on:

               -  Single probe average HER2 copy number ≥ 6 signals/cell

               -  Dual probe HER2/CEP 17 ratio ≥ 2.0 with an average HER2 copy number ≥ 4.0
                  signals/cell

               -  Dual probe HER2/CEP 17 ratio ≥ 2.0, with an average HER2 copy number of < 4.0
                  signals/cell

               -  Dual probe HER2/CEP 17 ratio < 2.0 with the average HER2 copy number of ≥ 6.0
                  signals/cell

          -  any ER or PR receptor status

          -  LVEF assessment by echocardiogram within 30 days of initiation; EF of ≥ 55% considered
             normal.

          -  Normal troponin I level at baseline

          -  Blood counts must meet the following criteria:

               -  ANC greater than or equal to 1500/mm3

               -  Platelet count greater than or equal to 100,000/mm3

               -  Hemoglobin greater than or equal to 10 g/dL

          -  Serum creatinine less than or equal 2.5 mg/100ml

          -  Adequate hepatic function by these criteria: total bilirubin must be less than or
             equal to 1.5 x the ULN for the lab unless the patient has a bilirubin elevation great
             than the 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 AST must be less than or equal to 1.5 x ULN for the lab. Both
             alkaline phosphatase and AST may not both be greater than the ULN.

          -  Patients with AST or alkaline phosphatase > ULN are eligible for inclusion in the
             study if liver imaging (CT, MRI, PET-CT or PET scan) performed within 90 days prior to
             randomization does not demonstrate metastatic disease and the requirements are met as
             above

          -  Patients with alkaline phosphatase that is > ULN but less than or equal to 2.5 x ULN
             or unexplained bone pain are eligible for inclusion in the study if a bone scan,
             PET-CT scan, or PET scan performed within 90 days prior to randomization does not
             demonstrate metastatic disease.

        Exclusion Criteria:

        Patients with a history of decompensated congestive heart failure or an EF < 55% will be
        excluded

        • Cardiac disease that would preclude the use of the drugs included in the above regimens.
        This includes but is not confined to:

          -  Active cardiac disease:

          -  angina pectoris requiring the use of anti-anginal medication;

          -  ventricular arrhythmias except for benign premature ventricular contractions
             controlled by medication;

          -  conduction abnormality requiring a pacemaker;

          -  supraventricular and nodal arrhythmias requiring a pacemaker or not controlled with
             medication; and

          -  clinically significant valvular disease

          -  symptomatic pericarditis

          -  pulmonary hypertension

          -  History of cardiac disease:

          -  myocardial infarction;

          -  congestive heart failure; or

          -  cardiomyopathy