A Phase II Study of Neoadjuvant Trastuzumab+Docetaxel+NPLD+/-Bevacizumab in Her2-pos. Early Breast Cancer

Study Overview
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Brief Summary
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Multicenter randomised phase II study of neoadjuvant therapy in HER2 positive early breast cancer. Primary aim is to evaluate the cardiac toxicity of the combined treatment (trastuzumab, docetaxel, bevacizumab, NPLD) in comparison to the standard therapy.

Detailed Description
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The target study population consists of male and female pre- and postmenopausal patients with HER2-positive, adenocarcinoma of the breast (except inflammatory breast cancer, T4d) scheduled to receive neoadjuvant cytotoxic treatment. Patients must have pathologically confirmed breast cancer with histologically confirmed HER2 over-expression. At screening, patients must have an adequate left ventricular ejection fraction (LVEF); an ECOG performance status of 0 or 1; adequate liver, renal and bone marrow function; and be free of other serious diseases that could affect protocol compliance or interpretation of results. Patients should not be at increased risk of GI perforation, hypertension, proteinuria, wound healing complications, thromboembolism or hemorrhage. Patients must not have had another primary malignancy that could affect compliance with the protocol or interpretation of results. Patients with central nervous system (CNS) metastases are excluded. Pregnant or lactating females are excluded. Patients with hypertension (>150 mmHG systolic or >100 mmHG diastolic) and patients with a history of GI perforation, abdominal fistula or intra-abdominal abscess within 6 months of study entry are excluded. Full anticoagulation therapy at study entry is allowed as long as the patient has been on a stable level of anticoagulants for at least 2 weeks at the time of study treatment start.

Official Title
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Multicentre Randomized Phase II Study of Neoadjuvant Trastuzumab Plus Docetaxel With and Without Bevacizumab and Trastuzumab Plus Docetaxel Plus Non-pegylated Liposome-encapsulated Doxorubicin (NPLD) With and Without Bevacizumab in HER2-positive Early Breast Cancer

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: Trastuzumab, Docetaxel
* Drug: Trastuzumab, Docetaxel, Bevacizumab
* Drug: Trastuzumab+Docetaxel+NPLD
* Drug: Trastuzumab+Docetaxel+NPLD+Bevacizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Female or male, age ≥ 18 years Pathologically confirmed invasive primary breast adenocarcinoma (except inflammatory breast cancer, T4d) scheduled for taxane containing neoadjuvant systemic treatment with/without palpable lymph nodes. Documented HER2 protein overexpression as determined by immunohistochemistry (IHC) 3+ or by demonstrated HER2/c-erbB2 gene amplification of the primary tumor by a local laboratory. LVEF ≥ 55% measured by echocardiography or MUGA within 4 weeks before randomization ECOG Performance Status ≤ 1 Able and willing to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures. Written Informed Consent Exclusion Criteria: Current Treatment Requirement for concurrent use of the antiviral agent sorivudine or chemically related analogues, such as brivudine. Chronic daily treatment with corticosteroids excl. inhaled steroids. Chronic daily treatment with aspirin and aspirin analogs or clopidogrel Major surgical procedure, open biopsy or significant traumatic injury within 28 days prior to randomization or anticipation of need for major surgery during the course of study treatment Current or recent (within 30 days prior to randomization) treatment with another investigational drug or participation in another investigational study. Laboratory Inadequate bone marrow function Inadequate liver function Inadequate renal function Patients not receiving anticoagulant medication who have activated partial thromboplastin time (aPTT) within 7 days prior to Day1 of the cycle 1. Concomitant Conditions Other malignancy within the last 5 years before randomization except for curatively treated carcinoma in situ of the cervix or non-melanomatous skin cancer Evidence of distant metastasis judged clinically and at least by chest-X-ray, liver-sonography and bone scan. If there is any clinical suspicion of brain metastasis, a CT-scan or MRI of the brain must be conducted within 4 weeks prior to randomization. Serious concurrent disease which could affect compliance with the protocol or interpretation of results, including, but not limited to: Active infection requiring i.v. antibiotics Uncontrolled hypertension Clinically significant history of cardiovascular disease as indicated by: cerebrovascular accident or stroke; myocardial infarction; unstable angina; NYHA Grade II or greater CHF; cardiac arrhythmia requiring medication; clinically significant valvular heart disease. Dyspnea at rest necessitating supportive oxygen therapy or with significant pleural effusions Poorly controlled diabetes mellitus History or evidence upon physical/neurological examination of CNS disease unrelated to cancer (e.g. uncontrolled seizures) unless adequately treated with standard medical therapy History or evidence of inherited bleeding diathesis or coagulopathy with the risk of bleeding History of abdominal fistula, GI perforation, or intra-abdominal abscess within 6 months of randomization Serious non-healing wound, peptic ulcer, or bone fracture Clinically significant malabsorption syndrome, ulcerative colitis, disease affecting GI function, resection of the stomach or small bowel, or inability to take oral medication Uncorrected hypokalemia or hypomagnesemia Organ allografts requiring immunosuppressive therapy Evidence of any other disease, metabolic or psychological dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug, may affect patient compliance with study routines, or place the patient at high risk from treatment related complications. Known hypersensitivity to any of the study drugs/excipients. Hypersensitivity to Chinese hamster ovary cell products or other recombinant human or humanized antibodies. Other Pregnant, lactating females or women of childbearing potential without a negative pregnancy test Fertile males or females of childbearing potential Patients not accessible for treatment or follow-up

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

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 |
| --- | --- |
| Other: A: Trastuzumab+Docetaxel<br> | Drug: Trastuzumab, Docetaxel<br>* 6 cycles - Day1 (Day22 = Day1): Trastuzumab: 8 mg/kg loading dose (1st cycle) i.v.; 6 mg/kg maintenance dose in subsequent cycles i.v. Docetaxel: 100 mg/m2 by 60 min i.v. infusion<br>* Other names: Therapy Arm A;|
| Experimental: B: Trastuzumab+Docetaxel+Bevacizumab<br> | Drug: Trastuzumab, Docetaxel, Bevacizumab<br>* 6 cycles - Day1 (Day22 = Day1): Trastuzumab: 8 mg/kg loading dose (1st cycle) i.v.; 6 mg/kg maintenance dose in subsequent cycles i.v. Docetaxel: 100 mg/m2 by 60 min i.v. infusion Bevacizumab 15 mg/kg<br>* Other names: Therapy Arm B;|
| Experimental: C: Trastuzumab+Docetaxel+NPLD<br> | Drug: Trastuzumab+Docetaxel+NPLD<br>* 6 cycles - Day1 (Day22=Day1): Trastuzumab: 8 mg/kg loading dose (1st cycle) i.v.; 6 mg/kg maintenance dose in subsequent cycles i.v. Docetaxel: 75 mg/m2 by 60 min IV infusion NPLD 50 mg/m2 by 60 min i.v. infusion<br>* Other names: Therapy Arm C;|
| Experimental: D: Trastuzumab+Docetaxel+NPLD+Bevacizumab<br> | Drug: Trastuzumab+Docetaxel+NPLD+Bevacizumab<br>* 6 cycles - Day1 (Day22= Day1): Trastuzumab: 8 mg/kg loading dose (1st cycle) i.v.; 6 mg/kg maintenance dose in subsequent cycles i.v. Docetaxel: 75 mg/m2 by 60 min i.v. infusion NPLD: 50 mg/m2 by 60 min i.v. infusion; Bevacizumab 15 mg/kg<br>* Other names: Therapy Arm D;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cardiac toxicity | to evaluate the cardiac toxicity of the combination trastuzumab+docetaxel+bevacizumab and trastuzumab+docetaxel+NPLD +/- bevacizumab in comparison to the standard therapy, trastuzumab+docetaxel using a composite endpoint appearing between day 1 of cycle 1 and day 28 after the day of final surgery. | between day 1 of cycle 1 and day 28 after the day of final surgery | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pathological complete response (ypCR) | ypCR defined as absence of invasive tumor at time of final surgery | up to 22 weeks | 
| Total pathological complete response (ytpCR) | ytpCR defined as absence of invasive tumor and tumor cells in the breast and the axillar lymphnodes (ypT0 or yDCIS and ypN=0) | up to 22 weeks | 
| Overall clinical response rate (cORR) | cORR defined as the percentage of patients with either a complete clinical response (cCR) or a partial clinical response (cPR), but no ypCR | up to 22 weeks | 
| Safety evaluation according to patients numbers of AEs, SAEs, lab test abnormalities, cardiac assessment, clinical evaluation | Safety (AEs, SAEs, lab test abnormalities, cardiac assessment, clinical evaluation)of the combination trastuzumab and docetaxel with bevacizumab and trastuzumab, docetaxel, and NPLD plus/minus bevacizumab at the time of final surgery | up to 22 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HER2-positive early breast cancer