Neoadjuvant Dose-Dense For Early Her2Neu Positive Breast Cancer

Study Overview
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Brief Summary
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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.

Official Title
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A Phase II Randomized Trial Evaluating Neoadjuvant Dose-Dense Doxorubicin/Cyclophosphamide Followed by Paclitaxel/Trastuzumab/Pertuzumab (AC THP) and Docetaxel/Carboplatin/Trastuzumab/Pertuzumab (TCHP) For Early Her2Neu Positive Breast Cancer

Conditions
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Locally Advanced Breast Cancer

Intervention / Treatment
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* Drug: Docetaxel
* Drug: Carboplatin
* Drug: Trastuzumab
* Drug: Pertuzumab
* Drug: Pegfilgrastim
* Drug: Trastuzumab
* Drug: Paclitaxel
* Drug: Doxorubicin
* Drug: Cyclophosphamide
* Drug: Paclitaxel


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: ddACTHP<br>Doxorubicin 60 mg/m2 IV day 1 Cyclophosphamide 600 mg/m2 IV day 1 Pegfilgrastim 6mg SC, day 2 of AC Cycled every 14 days for 4 cycles, followed by, Paclitaxel 80 mg/m2 IV x 1 hour infusion on days 1, 8, and 15 Trastuzumab 8 mg/kg IV day 1, followed by 6mg/kg Pertuzumab loading dose 840 mg IV followed by 420 mg IV every 3 weeks Cycled every 21 days for 4 cycles, followed by, Trastuzumab 6mg/kg every 21 days to complete 1 year | Drug: Pertuzumab<br>* Pertuzumab 840 mg IV initial dose followed by 420 mg IV, day 1<br>Drug: Trastuzumab<br>* Trastuzumab 6mg/kg every 21 days to complete 1 year<br>Drug: Paclitaxel<br>* 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.<br>Drug: Doxorubicin<br>* Doxorubicin 60 mg/m2 IV day 1<br>Drug: Cyclophosphamide<br>* Cyclophosphamide 600 mg/m2 IV day 1<br>Drug: Paclitaxel<br>* 80 mg/m2 IV x 1 hour infusion on days 1, 8, and 15<br>|
| Active Comparator: TCHP<br>TCHP (Docetaxel, Carboplatin, Trastuzumab, Pertuzumab, Pegfilgrastim ) institutional practice is to 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. | Drug: Docetaxel<br>* Docetaxel 75mg/m2 IV, day 1<br>Drug: Carboplatin<br>* Carboplatin AUC 6 IV, day 1<br>Drug: Trastuzumab<br>* Trastuzumab 8mg/kg IV initial dose, followed by 6mg/kg IV , day 1<br>Drug: Pertuzumab<br>* Pertuzumab 840 mg IV initial dose followed by 420 mg IV, day 1<br>Drug: Pegfilgrastim<br>* Pegfilgrastim 6mg SC, day 2 Cycled as per arm<br>Drug: Trastuzumab<br>* Trastuzumab 6mg/kg every 21 days to complete 1 year<br>Drug: Paclitaxel<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Pathologic Complete Response (pCR) | Pathologic complete response (pCR) defined as the absence of any residual invasive cancer on hematoxylin and eosin evaluation of the resected breast specimen and all sampled ipsilateral lymph nodes following completion of neoadjuvant systemic therapy. | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Cardiac Toxicity Events | Determination of cardiac toxicity as measured by LVEF, longitudinal strain and troponin. Left ventricular ejection fraction (LVEF) measurement of amount of blood being pumped out of the left ventricle of the heart with each contraction. Peak systolic longitudinal strain is calculated by averaging the values of peak systolic strain in the basal, mid and apical segments of the LV in 4-, 3- and 2-chamber views on echocardiograms. A value of <-18% or a >15% decline in strain from patient's baseline value will be used as a cut-off value. A value of troponin I > 0.08 ng/ml will be considered elevated. | 2 years | 
| Number of Non-cardiac Toxicities | The frequency of adverse events categorized using CTCAE v4.03 | 2 years | 
| Number of Participants With Breast Conservation | Number of participants with breast-conserving surgery for patients for whom mastectomy was planned before treatment. It would be based on surgical opinion at time of surgery if the tumor was appropriately downstaged to perform breast conserving surgery on patients previously recommended to have a mastectomy. | 2 years | 
| Number of Participants Alive at the End of the Study | Overall Survival - Number of participants alive at the end of the study. | 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Neoadjuvant chemotherapy, locally advanced breast cancer, Her2neu